@article {pmid42059045,
year = {2026},
author = {Xie, K and Jiang, Y and Chen, T and Liu, S and Fang, Y and Chen, F and Shen, J and Zeng, X and Li, P and Qiu, T and Wang, J and Yu, L and Zang, X and Wang, N and Yuan, J and Pang, H and Zhang, W and Ni, Z and Gu, L and Guo, Y and Lu, R},
title = {A prospective, randomized, double-blind, placebo-controlled, multicenter study of thiamin plus folic acid in the treatment of cognitive impairment in patients undergoing maintenance hemodialysis.},
journal = {Renal failure},
volume = {48},
number = {1},
pages = {2658981},
doi = {10.1080/0886022X.2026.2658981},
pmid = {42059045},
issn = {1525-6049},
mesh = {Humans ; *Thiamine/administration & dosage/therapeutic use/blood/adverse effects ; *Folic Acid/administration & dosage/therapeutic use/blood/adverse effects ; Female ; Male ; Double-Blind Method ; *Renal Dialysis/adverse effects ; Middle Aged ; *Cognitive Dysfunction/drug therapy/etiology/blood ; Prospective Studies ; Adult ; Aged ; Treatment Outcome ; *Kidney Failure, Chronic/therapy/complications ; Vitamin B Complex ; Young Adult ; Homocysteine/blood ; Adolescent ; },
abstract = {This prospective, randomized, double-blind, placebo-controlled trial investigated the efficacy and safety of thiamin and folic acid for cognitive impairment in maintenance hemodialysis (MHD) patients. A total of 215 MHD patients aged 18-75 with cognitive impairment were randomized to receive either oral thiamin (90 mg/day) plus folic acid (30 mg/day) or a placebo for 96 weeks. The primary endpoint was the change in the Alzheimer's Disease Assessment Scale-Cognitive section (ADAS-Cog) score. After 96 weeks, the treatment group showed a significant improvement in ADAS-Cog scores (from 21.25 ± 9.2 to 15.07 ± 8.38, p < 0.001), whereas the placebo group showed a non‑significant improvement (from 24.53 ± 11.01 to 26.53 ± 14.43, p = 0.077). The treatment group also demonstrated significantly increased blood levels of thiamin (from 5.59 ± 0.95 to 18.21 ± 3.91 ng/mL) and folate (from 12.37 ± 4.62 to 63.33 ± 16.02 ng/mL), and a reduction in homocysteine levels (from 4709.06 ± 353.15 to 2962.68 ± 158.87 ng/mL, p < 0.001), with no significant changes in the placebo group. While mortality was similar between the two groups (12.1% vs. 12.0%, p = 0.978), the incidence of adverse events was significantly lower in the treatment group (31.8% vs. 62.0%, p = 0.0017), particularly cardiovascular and cerebrovascular events (13.1% vs. 25.9%, p = 0.001). The study concludes that combined thiamin and folic acid supplementation improves cognitive function in MHD patients with a favorable safety profile.},
}

Humans
*Thiamine/administration & dosage/therapeutic use/blood/adverse effects
*Folic Acid/administration & dosage/therapeutic use/blood/adverse effects
Female
Male
Double-Blind Method
*Renal Dialysis/adverse effects
Middle Aged
*Cognitive Dysfunction/drug therapy/etiology/blood
Prospective Studies
Adult
Aged
Treatment Outcome
*Kidney Failure, Chronic/therapy/complications
Vitamin B Complex
Young Adult
Homocysteine/blood
Adolescent

@article {pmid42060857,
year = {2026},
author = {Mitchell, B and Harkess-Murphy, E and Douglas-Smith, N and Cheyne, J},
title = {Touch-Based Therapies in Dementia Care: A Systematic Review and Narrative Synthesis.},
journal = {Dementia (London, England)},
volume = {},
number = {},
pages = {14713012261445473},
doi = {10.1177/14713012261445473},
pmid = {42060857},
issn = {1741-2684},
abstract = {Touch-based therapies (massage, acupressure, reflexology/shiatsu, and therapeutic/healing touch) are used in dementia care, but effectiveness remains uncertain. The authors evaluated their impact on behavioural and psychological symptoms of dementia (BPSD) and pain, and extracted pragmatic "dose" and delivery parameters to inform a research blueprint. The authors searched major databases (MEDLINE, CINAHL, PsycINFO, Embase, CENTRAL) for studies from January 2005 to February 2023 involving people with any dementia aetiology/severity in community, residential, or inpatient settings. Eligible designs included randomised, quasi-experimental, and pre-post studies with a comparator (usual care, attention/quiet presence, or sham/light-touch). Data were extracted to a prespecified template; study quality was appraised using CASP tools. Owing to substantial clinical and methodological heterogeneity, the authors conducted a structured narrative synthesis as opposed to meta-analysis. Thirty-three studies met inclusion: 21 massage, 8 acupressure, 3 therapeutic/healing touch, and 2 reflexology/shiatsu. Most were in long-term care or inpatient settings. Interventions typically used brief, repeated sessions (5-20 minutes, several times per week for 2-6 weeks). The most consistent finding was short-term calming, particularly reductions in agitation immediately post-session or over brief treatment courses, with the clearest pattern for massage and acupressure. Effects on broader neuropsychiatric symptoms (e.g., NPI/NPI-NH domains) and pain were mixed. Where monitored, no serious adverse events were reported; minor transient issues (e.g., brief restlessness, skin sensitivity with aromatherapy oils) were infrequent and acceptability generally high. Risk of bias was mixed (≈49% low, 42% moderate, 9% high), and durability beyond 4-8 weeks was rarely assessed. Current evidence provides preliminary indications that brief, touch-based therapies may offer short-term calming effects when used alongside person-centred care, although certainty remains low and findings should be interpreted cautiously. The authors propose a pragmatic research blueprint that predefines session length, frequency, and course duration; uses attention/sham controls; adopts core outcomes (e.g., Cohen Mansfield Agitation Inventory (CMAI), Neuropsychiatric Inventory/Neuropsychiatric Inventory adapted for Nursing Homes (NPI/NPI-NH); Pain Assessment in Advanced Dementia (PAINAD) where relevant); ensures blinded assessment; and extends follow-up. The authors recommend that future work should prioritise feasibility/pilot studies, followed by adequately powered trials to determine effectiveness, durability, and scalability for practice.},
}

@article {pmid42060990,
year = {2026},
author = {Hsu, YH and Liang, CK and Chou, MY and Davidson, J and Wang, YC and Nalls, MA and Ferrucci, L and Cookson, M and Iwaki, H},
title = {Amyloid pathology and modifiable risk factors in cognitive decline among cognitively unimpaired older adults.},
journal = {The journal of prevention of Alzheimer's disease},
volume = {13},
number = {6},
pages = {100574},
doi = {10.1016/j.tjpad.2026.100574},
pmid = {42060990},
issn = {2426-0266},
abstract = {BACKGROUND: Alzheimer's disease (AD) pathology, particularly amyloid-β (Aβ) deposition, occurs years before clinical symptoms. Modifiable risk factors may influence cognitive trajectories during this preclinical stage, but whether amyloid status alters their effects remains unclear.

OBJECTIVES: To investigate interactions between amyloid pathology and modifiable risk factors in predicting longitudinal cognitive decline among cognitively unimpaired older adults.

DESIGN AND SETTING: This study was a secondary analysis of data derived from two large multicenter longitudinal cohort studies, the Anti-Amyloid Treatment in Asymptomatic Alzheimer Disease (A4) Study and the Longitudinal Evaluation of Amyloid Risk and Neurodegeneration (LEARN) Study.

PARTICIPANTS: A total of 1707 cognitively unimpaired adults aged 65-85 years were included, comprising 1169 amyloid-positive participants from the A4 Study (Aβ+) and 538 amyloid-negative participants from the LEARN Study (Aβ-).

MEASUREMENTS: Cognitive function was assessed every six months using the Preclinical Alzheimer's Cognitive Composite (PACC) over a mean follow-up of 4.9 years. Eight established modifiable risk factors-low education, alcohol use, diabetes, high cholesterol, high blood pressure, obesity, depressive symptoms, and physical inactivity-were evaluated. Linear mixed-effects models were applied to examine associations between each risk factor and longitudinal PACC decline, and to test interactions with amyloid status, adjusting for demographic and genetic covariates.

RESULTS: Significant interactions between amyloid status and modifiable risk factors were observed for diabetes (adjusted β = -0.206, p = 0.032), high cholesterol (adjusted β = -0.155, p < 0.001), and physical inactivity (adjusted β = -0.161, p = 0.046), indicating combined effects rather than additive effects on cognitive decline among Aβ+ individuals. In the A4 study (Aβ+), low education, diabetes, high cholesterol, and physical inactivity were independently associated with accelerated cognitive decline, whereas obesity was linked to slower decline. In contrast, in the LEARN study (Aβ-), these associations were not statistically significant.

CONCLUSIONS: In conclusion, the significant interactions with amyloid status were observed for diabetes, high cholesterol, and physical inactivity, indicating that these risk factors were associated with faster cognitive decline specifically in Aβ+ individuals. The results suggest that consideration of amyloid status may be important when evaluating the potential role of metabolic and lifestyle risk factors in preclinical cognitive decline. In Aβ+ individuals, obesity was associated with slower cognitive decline, while low education was linked to lower baseline cognition or a reduced symptom threshold, without a significant interaction with amyloid status. Future studies should incorporate amyloid status and longitudinal biomarkers to assess whether modifying these factors can slow preclinical cognitive decline.},
}

@article {pmid42062795,
year = {2026},
author = {Li, L and Yang, M and Tao, J and Zhao, Y and Zhao, N and Sun, S},
title = {Kaempferol Improves Alzheimer's Disease by Inhibiting Neuronal Ferroptosis via Activating GPX4/AKR1C3 Signaling Pathway.},
journal = {Pharmacology research & perspectives},
volume = {14},
number = {3},
pages = {e70255},
doi = {10.1002/prp2.70255},
pmid = {42062795},
issn = {2052-1707},
support = {2022ZD050//Corps Guiding Science and Technology Projects/ ; 2025DA013//Scientific and technological research projects in key fields of the Corps/ ; },
mesh = {Animals ; *Alzheimer Disease/drug therapy/metabolism ; *Ferroptosis/drug effects ; *Kaempferols/pharmacology/therapeutic use ; PC12 Cells ; Rats ; Signal Transduction/drug effects ; Amyloid beta-Peptides/metabolism ; *Phospholipid Hydroperoxide Glutathione Peroxidase/metabolism ; Mice ; Male ; Neurons/drug effects/metabolism ; Disease Models, Animal ; NF-E2-Related Factor 2/metabolism ; Peptide Fragments ; Mice, Inbred C57BL ; *Neuroprotective Agents/pharmacology ; Humans ; },
abstract = {Kaempferol has been shown to be beneficial in the treatment of Alzheimer's disease (AD) in animal models. However, the action mechanism remains unclear. AKR1B1 has been identified as a target of kaempferol, initially suggested by the Therapeutic Target Database, DrugBank, and PubChem, and subsequently confirmed through experimental validation. Kaempferol treatment facilitated the expression of AKR1B1 in PC12 cells exposed to Aβ1-42. Kaempferol treatment mitigated the Aβ1-42-induced increases in Fe[2+], MDA, and lipid ROS and Aβ1-42-induced decreases in GSH synthesis and SOD activity. The reduction in ferroptosis-related proteins (GPX4, NQO1, SLC7A11, AKR1C1, and AKR1C3) and the inhibition of Nrf2 nuclear translocation and Nrf2/HO-1 signaling caused by Aβ1-42 were also reversed by kaempferol. Overexpressing AKR1B1 led to decreased levels of Fe[2+], MDA, and lipid ROS, along with increased GSH synthesis and SOD activity in Aβ1-42-treated cells, although these effects were negated by Nrf2 inhibition. The upregulation of GPX4 and AKR1C3 by AKR1B1 overexpression was also reversed when Nrf2 expression was inhibited. Notably, silencing AKR1B1 counteracted the protective effects of kaempferol against Aβ1-42-induced neuronal ferroptosis. In vivo studies revealed that kaempferol improved cognitive impairments, reduced deposition of Aβ and p-Tau, and alleviated neuronal ferroptosis in the hippocampal tissues of an AD mouse model in a dose-dependent manner, effects that were diminished by inhibiting AKR1B1 expression. Following kaempferol treatment, the levels of GPX4 and AKR1C3 in the hippocampus of AD mice were found to be reduced. Overall, our findings indicate that kaempferol treatment enhances cognitive function and mitigates pathological alterations in AD mice by inhibiting neuronal ferroptosis through the activation of the Nrf2/HO-1/GPX4/AKR1C3 signaling via upregulation of AKR1B1. This research supports the need for further investigation and clinical exploration of kaempferol.},
}

Animals
*Alzheimer Disease/drug therapy/metabolism
*Ferroptosis/drug effects
*Kaempferols/pharmacology/therapeutic use
PC12 Cells
Rats
Signal Transduction/drug effects
Amyloid beta-Peptides/metabolism
*Phospholipid Hydroperoxide Glutathione Peroxidase/metabolism
Mice
Male
Neurons/drug effects/metabolism
Disease Models, Animal
NF-E2-Related Factor 2/metabolism
Peptide Fragments
Mice, Inbred C57BL
*Neuroprotective Agents/pharmacology
Humans

@article {pmid42063485,
year = {2026},
author = {Huang, Y and Xu, J and Fan, Z and Hu, Y and He, X and Chen, A and Liu, Y and Yin, R and Guo, J and DeKosky, ST and Jaffee, M and Zhou, M and Su, C and Wang, F and Guo, Y and Bian, J},
title = {Identifying Alzheimer's Disease Progression Subphenotypes Via a Graph-based Framework Using Electronic Health Records.},
journal = {Journal of healthcare informatics research},
volume = {},
number = {},
pages = {},
pmid = {42063485},
issn = {2509-4971},
abstract = {Understanding the heterogeneity of neurodegeneration in Alzheimer's disease (AD) and identifying distinct progression pathways is critical for improving diagnosis, treatment, prognosis, and prevention. Motivated by this need, this study aimed to identify disease progression subphenotypes among patients with mild cognitive impairment (MCI) and AD using electronic health records (EHRs). We developed a novel approach that combines a graph neural network (GNN)-based framework with time series clustering to characterize progression subphenotypes from MCI to AD. We applied the proposed framework to a real-world cohort of 2,525 patients (61.66% female; mean age 76 years), of whom 64.83% were Non-Hispanic White, 16.48% Non-Hispanic Black, 2.53% were of other races, and 10.85% were Hispanic. Our model identified four distinct progression subphenotypes, each exhibiting characteristic clinical patterns, with average MCI-to-AD progression times ranging from 805 to 1,236 days. These findings indicate that AD does not follow a uniform progression trajectory but instead manifests heterogeneous pathways, and the proposed framework provides an explainable, data-driven approach for delineating AD progression subphenotypes, offering actionable insights for healthcare informatics research and the clinical management of patients at risk for AD.},
}

@article {pmid42063523,
year = {2025},
author = {Fitri, FI and Rambe, AS and Effendy, E and Kadri, A and Prawiroharjo, P and Lubis, IND and Surbakti, KP and Amin, MM and Rusda, M and Gustianingsih, },
title = {Instrument for Assessment of Neurodegenerative Aphasia in Indonesia or Instrumen Afasia Neurodegeneratif Indonesia (IRFANI): Development and pilot study.},
journal = {Journal of Alzheimer's disease reports},
volume = {9},
number = {},
pages = {25424823251366640},
pmid = {42063523},
issn = {2542-4823},
abstract = {BACKGROUND: Primary progressive aphasia (PPA) is a neurodegenerative disorder causing progressive language impairment. Early diagnosis is crucial for treatment planning, yet no standardized assessment exists for Indonesian speakers.

OBJECTIVE: This study describes the initial development of the Instrumen Afasia Neurodegeneratif Indonesia (IRFANI), focusing on test construction, content validity, and pilot testing.

METHODS: IRFANI was designed to assess syntax, motor speech, semantics, and phonology, following Gorno-Tempini et al. (2011) diagnostic criteria. The blueprint covered key domains, including confrontation naming (nouns/verbs), sentence production/comprehension, single-word comprehension, semantic association, and repetition tasks. Verbal stimuli were selected based on expert input and Indonesian word frequency lists, while custom black-and-white illustrations ensured linguistic and cultural relevance. Five neurobehavioral neurologists assessed content validity using Aiken's Content Validity Index (CVI). A pilot study was conducted with 30 participants diverse in age, sex, education, and ethnicity.

RESULTS: Expert consultations refined the test blueprint. Qualitative analysis identified ambiguous images, multiple correct answers, and unclear phrasing in naming and sentence tasks. Issues included visually similar images and ambiguous sentence structures. Quantitative validation (CVI = 0.9) confirmed strong expert agreement, with items scoring below 0.8 excluded. The pilot study demonstrated good reliability (0.923) and provided insights for further refinement.

CONCLUSIONS: IRFANI was systematically developed through expert validation, pilot testing, and iterative refinement, ensuring clarity and strong content validity. Further studies are needed to confirm its construct validity, reliability, and diagnostic accuracy.},
}

@article {pmid42065636,
year = {2026},
author = {Behler, C and Fay, M and Ramadan, S and Breakspear, M and Behler, A},
title = {Neurophysiology of brain temperature dysregulation in humans.},
journal = {Journal of neurophysiology},
volume = {},
number = {},
pages = {},
doi = {10.1152/jn.00418.2025},
pmid = {42065636},
issn = {1522-1598},
support = {//Tour de Cure (TDC)/ ; //Mark Hughes Foundation Centre for Brain Cancer Research/ ; },
abstract = {Brain temperature, a fundamental modulator of neural function, remains dramatically understudied despite its critical role in health and disease. This review synthesizes current understanding of brain thermoregulation and its disruption in neurological conditions, addressing a significant knowledge gap in neuroscience. We examined the physiological mechanisms maintaining brain temperature homeostasis, including the interplay between cerebral blood flow, metabolism, and cerebrospinal fluid dynamics. Analysis of publication trends reveals brain temperature research is underrepresented by 7- to 37-fold compared to other brain physiological parameters, despite comparable clinical relevance. We evaluated current non-invasive measurement techniques, particularly magnetic resonance-based thermometry, highlighting advances and limitations for clinical application. The review presents evidence for distinct temperature dysregulation patterns in neurological diseases. In Alzheimer's disease, we propose a theoretical framework of early-stage hyperthermia driven by neuroinflammation and hypermetabolism, transitioning to late-stage hypothermia with metabolic decline. Brain tumors exhibit contrasting thermal profiles: glioblastomas frequently present as hypothermic due to necrotic cores acting as metabolic voids, while melanoma metastases show hyperthermia from sustained metabolic activity. These temperature alterations may influence disease progression through effects on protein aggregation, cellular metabolism, and neuron-glial interactions. Looking forward, brain temperature monitoring could provide biomarkers for disease staging and treatment response. Additionally, understanding thermal limits becomes urgent as climate change exposes vulnerable populations with compromised thermoregulation to extreme heat. This review establishes brain temperature as an overlooked but essential axis in neurophysiology, calling for increased research attention to address fundamental questions about thermal regulation in health and disease.},
}

@article {pmid42066672,
year = {2026},
author = {Mast, N and Bederman, I and El-Darzi, N and Pikuleva, IA},
title = {CYP46A1 activation by low-dose efavirenz uncovers the link between brain cholesterol metabolism, energetics, and vasculature.},
journal = {Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie},
volume = {199},
number = {},
pages = {119470},
doi = {10.1016/j.biopha.2026.119470},
pmid = {42066672},
issn = {1950-6007},
abstract = {CYP46A1 converts cholesterol to 24-hydroxycholesterol, the principal mechanism for brain cholesterol removal and turnover. CYP46A1 can be allosterically activated with low-dose anti-HIV drug efavirenz and mitigate the manifestations of various neurologic diseases in mouse models and Niemann-Pick type C disease in humans. Yet the underlying reasons for such a broad range of efavirenz therapeutic effects are currently unknown. Here 5XFAD mice, a model of Alzheimer's disease, were treated with low-dose efavirenz, and assessed for changes in their brain proteome, acetylproteome, and metabolome. Sex-independent increases in brain levels of phosphatidylcholines, sphingomyelins, and certain amino acids were documented, and various functional enrichments were identified. The most notable related to brain energy production, vascularization, and prevention of glutamatergic overactivation. Unexpectedly, these and many other enrichments were mediated by different proteins in female and male 5XFAD mice. Efavirenz treatment of 5XFAD mice was repeated, and energy-related compounds were quantified in the brain after in vivo isotopic labeling. Cerebral vasculature was assessed as well. We found increased glycolysis branching, carbon flux through the tricarboxylic acid cycle, and use of alternative energy sources (fatty acids, ketone bodies, and amino acids). Sex-independent improvements in brain vascularization and integrity of the blood-brain barrier were also documented. Collectively, our data suggested that CYP46A1 activation by efavirenz increases brain metabolic flexibility and thereby brain energetics. This enables the increase in production of the building blocks for cellular and tissue repair and rescue of brain pathology, thus explaining the therapeutic benefits for the broad spectrum of neurologic disorders.},
}

@article {pmid39835867,
year = {2025},
author = {Rongve, A and Årsland, D and Fladby, T and Øksengård, AR and Selbæk, G},
title = {[New era in the treatment and diagnosis of Alzheimer’s disease].},
journal = {Tidsskrift for den Norske laegeforening : tidsskrift for praktisk medicin, ny raekke},
volume = {144},
number = {1},
pages = {},
doi = {10.4045/tidsskr.24.0604},
pmid = {39835867},
issn = {0807-7096},
}

@article {pmid41653394,
year = {2026},
author = {Okuyama, C and Oishi, N and Ishizu, K and Hasegawa, H and Ito, M and Fujita, Y and Kusano, K and Okina, T and Kagawa, S and Watanabe, H and Higashi, T and Yamauchi, H and Ono, M},
title = {A new amyloid PET evaluation method using separated gray-matter histogram based on three-component model.},
journal = {Annals of nuclear medicine},
volume = {40},
number = {5},
pages = {564-574},
pmid = {41653394},
issn = {1864-6433},
support = {KAKENHI (JSPS Grant Number JP21K07635).//Japan Society for the Promotion of Science/ ; },
abstract = {OBJECTIVE: We have constructed a three-component model underlying amyloid PET accumulation and developed a new gray matter histogram evaluation method based on this model. This study aims to validate the utility of the new method compared with conventional visual and SUVR-based quantitative evaluation.

METHODS: A retrospective analysis was performed on amyloid PET/CT data from 63 participants (25 healthy volunteers, 38 patients with dementia or cognitive impairment) of previous study using [18]F-FPYBF-2. Subjects were visually classified into three groups: negative, borderline, and positive, and quantitatively evaluated using composed standardized uptake value (comSUVR) with a reference to cerebellar cortex. Histograms were generated for the whole-brain, gray matter (GM-histogram), and white matter (WM-histogram) based on probability-tissue maps. The GM-histogram was further decomposed into two Gaussian components: G1 and G2　using statistical software. Parameters of whole-brain histogram: skewness, mode-to-mean ratio (MMR), and parameters of GM-histogram: GM-kurtosis, µG2 (mean of G2), and πG2 (proportion of G2), were compared among visual groups and the correlation with comSUVR was evaluated.

RESULTS: The GM-histogram was sharply unimodal in visually negative group but showed a wide shape to bimodal patterns in visually positive cases. Visually border group showed significantly higher πG2 than negative group, and positive group showed significantly higher µG2 than border group. GM-kurtosis and µG2 showed stronger negative (p < 0.0001, R[2] = 0.7539) and positive (p < 0.0001, R[2] = 0.8589) correlations with ComSUVR, respectively than the correlations between whole-brain histogram parameters and ComSUVR.

CONCLUSION: Our proposed GM-histogram provides a visually comprehensive morphology and quantitative indicators that match conventional visual and SUVR-based assessments and may potentially detect even subtle amyloid accumulation. This method is considered promising as a complementary tool for early diagnosis and treatment monitoring of Alzheimer’s disease.},
}

@article {pmid41862963,
year = {2026},
author = {Zhang, YY and Huang, NN and Li, XH and Zuo, J and Fan, YC},
title = {Dysfunctional astrocytes regulate excitatory neurons via cell adhesion and vascular lesions in patients with Alzheimer's disease.},
journal = {Journal of translational medicine},
volume = {24},
number = {1},
pages = {},
pmid = {41862963},
issn = {1479-5876},
support = {2024CXGC010604//Key Technology Research and Development Program of Shandong Province/ ; 2021SDUCRCB006//ECCM Program of Clinical Research Centre of Shandong University/ ; },
abstract = {BACKGROUND: Alzheimer’s disease (AD) is a progressive neurodegenerative disorder. Its complex pathogenesis remains unclear, and no specific drugs are available for treatment. Current treatments focus mainly on delaying progression and managing symptoms, a situation that highlights the urgent need for deeper exploration of the pathogenic mechanisms.

METHODS: We retrieved seven datasets (GSE174367, GSE122063, GSE48350, GSE5281, GSE28146, GSE222494, and GSE221365) from the GEO database and performed multi-omics analyses at the transcriptome, single-cell transcriptome, and spatial transcriptome levels.

RESULTS: We identified significant cellular heterogeneity in the frontal cortex when comparing data from the AD group with data from the control group. The combined results of enrichment analyses at the single-cell and transcriptome levels confirmed that AD pathogenesis involves the dysregulation of multiple pathways. Further studies revealed that dysfunctional regulation of neurogenesis, neuropathic immunity, and neural signal transduction could be attributed primarily to astrocytes (ASCs). Cell communication analysis indicated that ASCs may regulate excitatory neurons (ExNs) through via cell adhesion molecule 1 (CADM1) interactions. Additionally, we identified three signature subpopulations of ASCs and a signature gene module, ADr1, as potential biomarkers. Finally, spatial transcriptome analysis revealed the spatial distributions of different cells and potential vascular lesions from AD patients, consistent with the transcriptome results.

CONCLUSION: Our integrative analysis reveals a strong association between ASC dysfunction and impaired ExNs states, potentially mediated by elevated CADM1-dependent adhesion. This interaction may represent a compensatory mechanism or a contributor to neuronal vulnerability in AD. The findings further support the presence of vascular lesions in AD.

SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12967-026-08027-y.},
}

@article {pmid41862970,
year = {2026},
author = {Gea-González, A and Valle-Pedroso, R and López-Font, I and Zetterberg, H and Blennow, K and Sáez-Valero, J and García-Ayllón, MS},
title = {Selective reduction of ADAM10 in brain and cerebrospinal fluid of Alzheimer's disease patients.},
journal = {Alzheimer's research & therapy},
volume = {18},
number = {1},
pages = {},
pmid = {41862970},
issn = {1758-9193},
support = {CIACIF/2021/426//Conselleria of Education, Culture, Universities and Employment/ ; 2019/20110-1 and #2017/18808-5//São Paulo Research Foundation/ ; #ADSF-21-831376-C, #ADSF-21-831381-C, #ADSF-21-831377-C, and #ADSF-24-1284328-C//Swedish Research Council/ ; #2017-00915 and #2022-00732//Swedish Research Council/ ; NEuroBioStand, #22HLT07//European Partnership on Metrology/ ; #FO2022-0270//Bluefield Project, Cure Alzheimer's Fund, the Olav Thon Foundation, the Erling-Persson Family Foundation, Familjen Rönströms Stiftelse, Stiftelsen för Gamla Tjänarinnor, Hjärnfonden/ ; 860197 (MIRIADE)//H2020 Marie Skłodowska-Curie Actions/ ; JPND2021-00694//European Union Joint Programme - Neurodegenerative Disease Research/ ; UKDRI-1003//National Institute for Health and Care Research University College London/ ; #AF-930351, #AF-939721, #AF-968270, and #AF-994551//Swedish Alzheimer Foundation/ ; #ALZ2022-0006, #FO2024-0048-TK-130 and FO2024-0048-HK-24//Hjärnfonden/ ; #ALFGBG-965240 and #ALFGBG-1006418//ALF-agreement/ ; JPND2019-466-236//European Union Joint Program for Neurodegenerative Disorders/ ; ZEN-21-848495//Alzheimer's Association 2021 Zenith Award/ ; SG-23-1038904 QC//Alzheimer's Association 2022-2025 Grant/ ; PI22/01329//Fondo de Investigaciones Sanitarias/ ; PI24/01421//Fondo de Investigaciones Sanitarias/ ; CIAICO/2024/313//Direcció General de Ciència i Investigació, Generalitat Valenciana/ ; UGP-21-217//Fundación para el Fomento de la Investigación Sanitaria y Biomédica de la Comunitat Valenciana/ ; },
abstract = {BACKGROUND: ADAM10 and ADAM17, members of the membrane-bound disintegrin metalloproteinase (ADAM) family, act as α-secretases in the non-amyloidogenic processing of the amyloid precursor protein. While alterations in ADAM10, the primary α-secretase, have been reported in Alzheimer’s disease (AD), with certain controversy between studies, ADAM17 changes remain less understood. Both enzymes display a complex pattern of expression that includes immature zymogen and mature full-length, assigned as the active form, and soluble cleaved species. We reported for the first time that ADAM10 is present in human cerebrospinal fluid (CSF), and levels of the full-length and soluble fragments decrease in samples from AD patients.

METHODS: ADAM10 and ADAM17 levels were determined in human samples from frontal cortex (Brodmann areas 9/10) from histopathologically-confirmed AD cases (n = 16) and non-dementia controls (n = 13), and in CSF from individuals with cognitive symptoms and an AD-consistent biomarker profile (n = 20) and from controls with normal biomarker parameters (n = 18). Levels were also assessed in SH-SY5Y cells differentiated to neurons, after 48 h of 3 µM Aβ42 treatment. Protein species were resolved by electrophoresis followed by quantitative fluorescent western blotting. Significant differences between AD and control groups were evaluated using Student’s unpaired t-test or the Mann–Whitney U test, as appropriate.

RESULTS: We confirm the significant reduction in levels of mature and soluble ADAM10 species in lumbar CSF of AD patients. We also validate in postmortem AD brain the decrease in mature species of ADAM10 with no change in the levels of its zymogen nor mRNA transcript, suggesting a post-translational dysregulation in the production of active protein. In contrast, ADAM17 levels remained unchanged in both brain and CSF samples, highlighting a differential regulation between these two α-secretases in AD pathology. In SH-SY5Y-differentiated neurons, treatment with Aβ42 also led to a specific reduction in mature ADAM10, implicating Aβ in the disruption of ADAM10 maturation.

CONCLUSIONS: Our study links a compromise in α-secretase to AD pathology. It demonstrates a selective reduction of the mature forms of ADAM10 in AD that may contribute to an impaired non-amyloidogenic APP processing. Aβ42 appears to be a key modulator of this dysfunction, suggesting that ADAM10 downregulation may be an early event in AD pathogenesis. The results don’t evidence any major role for ADAM17 in AD pathogenesis.},
}

@article {pmid41864901,
year = {2026},
author = {Kim, N and Kahm, SH},
title = {Association between dental implants and health outcomes in Korean patients with dementia: a retrospective cohort study.},
journal = {BMC oral health},
volume = {26},
number = {1},
pages = {},
pmid = {41864901},
issn = {1472-6831},
abstract = {BACKGROUND: Alzheimer’s disease (AD) is a growing global health concern, and emerging evidence suggests that oral health—particularly tooth loss—may be linked to cognitive decline. While implant therapy effectively restores oral function, its systemic health implications in dementia patients have not been fully investigated.

METHODS: We retrospectively analyzed 1,445 dementia patients treated at two tertiary hospitals in Korea between 2011 and 2020. Clinical data, panoramic radiographs, and laboratory biomarkers were assessed to compare systemic and oral health outcomes between implant and non-implant groups. Statistical analyses included parametric and nonparametric tests with Bonferroni post-hoc validation.

RESULTS: Baseline demographics were similar between groups. Mortality was lower in the implant group (10.6% vs. 15.6%, p = 0.014). Laboratory markers showed statistically significant but clinically modest differences in serum calcium (8.90 vs. 8.78 mg/dL) and C-reactive protein (1.94 vs. 2.17 mg/dL). Oral health outcomes were significantly superior in implant recipients, including more remaining teeth (23.4 vs. 19.7) and greater posterior occlusal support (all p < 0.05).

CONCLUSIONS: Dental implant therapy in dementia patients was associated with lower mortality and superior oral health. However, these associations likely reflect inherent selection bias and better healthcare access among implant recipients rather than direct treatment effects. Prospective longitudinal studies with neurocognitive assessments are required to confirm potential causal relationships.},
}

@article {pmid42055498,
year = {2026},
author = {Zheng, W and Zhou, Y and Lu, M and Wang, Y},
title = {Associations of obstructive sleep apnea with A/T/N biomarkers, neuroimaging abnormalities, neurodegenerative progression, and CPAP-related changes in Alzheimer's disease.},
journal = {Sleep medicine},
volume = {144},
number = {},
pages = {108975},
doi = {10.1016/j.sleep.2026.108975},
pmid = {42055498},
issn = {1878-5506},
abstract = {BACKGROUND: Obstructive sleep apnea (OSA) has been increasingly linked to cognitive impairment and dementia, yet its relationship with core Alzheimer's disease (AD) pathology, multimodal brain injury, longitudinal neurodegenerative progression, and potential treatment responsiveness remains incompletely understood.

METHODS: Cross-sectional analyses compared amyloid/tau/neurodegeneration (A/T/N) biomarkers and multimodal neuroimaging measures between groups, including cerebrospinal fluid (CSF) biomarker quantification, amyloid positron emission tomography (PET), structural MRI, white matter imaging, the diffusion tensor imaging analysis along the perivascular space (DTI-ALPS) index, and choroid plexus volume, the latter two used as indirect imaging markers reflecting potential alterations in glymphatic-related fluid transport and waste-clearance pathways. Among OSA participants who initiated continuous positive airway pressure (CPAP) therapy, changes over the approximately 6-month follow-up period were compared according to adherence status.

RESULTS: Compared with patients without OSA, those with OSA showed a more adverse A/T/N biomarker profile, including lower CSF Aβ42 (528.19 ± 147.83 vs 612.37 ± 158.46 pg/mL), lower CSF Aβ42/40 ratio (0.064 ± 0.013 vs 0.071 ± 0.014), higher amyloid PET SUVR (1.38 ± 0.21 vs 1.24 ± 0.18), higher CSF p-tau181 (74.92 ± 26.15 vs 63.48 ± 21.37 pg/mL), higher plasma NfL (31.79 ± 13.27 vs 24.68 ± 10.42 pg/mL), and higher plasma GFAP (233.47 ± 104.26 vs 196.54 ± 82.71 pg/mL). Neuroimaging analyses further showed smaller hippocampal volume, greater white matter injury, a lower DTI-ALPS index (1.27 ± 0.18 vs 1.43 ± 0.19), and a larger choroid plexus volume (3291.73 ± 768.61 vs 2814.56 ± 712.48 mm[3]) in the OSA group. Longitudinally, OSA was associated with faster annual increases in NfL (2.37 vs 0.72 pg/mL/year) and GFAP (15.19 vs 4.54 pg/mL/year), as well as faster hippocampal atrophy over time. Among treated participants, CPAP adherence was associated with improved cognition (MoCA: +0.59; ADAS-Cog: -1.48) and reductions in IL-6 (-0.95 pg/mL), GFAP (-14.67 pg/mL), and NfL (-2.33 pg/mL).

CONCLUSIONS: In patients with AD, OSA was associated with a more adverse A/T/N biomarker profile, broader neuroimaging abnormalities, including altered DTI-ALPS index and choroid plexus volume as indirect imaging markers of potential glymphatic-related dysfunction, and faster neurodegenerative progression. CPAP adherence was associated with more favorable short-term trajectories, suggesting that OSA may be a clinically relevant and potentially modifiable contributor to disease burden in AD.},
}

@article {pmid42055956,
year = {2026},
author = {Ivanidze, J and Gardella, J and Olson, A and Sun, SM and Thomas, C and Wong, OL and Intorcia, B and Moirano, J and Tanavde, V and Gershon, B and Pahlajani, S and Roytman, M and Nordvig, A and Lin, M and Hamed, M and Alport, A and Salgado, M and Keil, S and O'Dwyer, E and Lantos, J and Huicochea Castellanos, S and Ebani, EJ and Agee, M and Fink, ME and Osborne, JR and Chiang, GC and Blum, S},
title = {PET-guided Assessment of Amyloid Clearance and Outcomes in a Real-World Cohort of Patients with Alzheimer Disease undergoing Anti-Amyloid Therapy.},
journal = {AJNR. American journal of neuroradiology},
volume = {},
number = {},
pages = {},
doi = {10.3174/ajnr.A9387},
pmid = {42055956},
issn = {1936-959X},
abstract = {BACKGROUND AND PURPOSE: Beta-amyloid (Aβ)-PET is central to confirming Alzheimer disease (AD) before treatment with anti-amyloid monoclonal antibody therapies (AAT), however its role in treatment response monitoring in routine clinical practice remains unclear. This study aimed to evaluate longitudinal Aβ-PET changes following AAT and their association with clinical and safety outcomes in a real-world cohort.

MATERIALS AND METHODS: We conducted a retrospective single-center study of patients with mild cognitive impairment (MCI) or mild dementia due to AD who underwent Aβ-PET before and after treatment with AAT (lecanemab or donanemab). Aβ-PET scans were assessed using visual interpretation and quantitative measures including Centiloid level (CL) and regional Z-scores. Treatment-related amyloid clearance (TRAC) was determined based on magnitude of CL changes (ΔCL). Associations between Aβ-PET changes and baseline Fazekas score, amyloid-related imaging abnormalities (ARIA) and APOE-ε4 carrier status were examined. Associations between ΔCL and cognitive performance from baseline to post-AAT as assessed per Mini-Mental State Examination (ΔMMSE) were examined using multivariable linear regression models incorporating baseline CL and adjusting APOE-ε4 status and occurrence of ARIA. Region-specific multivariable analyses evaluated associations between regional Z-score changes and ΔMMSE.

RESULTS: Thirty-two patients met inclusion criteria (lecanemab, N=15; donanemab, N=17). Significant Aβ reduction was observed across the cohort (median ΔCL 59.11; p < 0.001) as well as within each treatment group. Most patients meeting TRAC criteria achieved full or partial TRAC (26/29, 89.7%). Baseline Aβ burden, as well as cognitive outcomes, did not differ significantly across TRAC categories (p = 0.25). ΔCL was not significantly associated with APOE-ε4 status or ARIA occurrence. In adjusted analyses, greater global CL reduction was associated with greater MMSE improvement, particularly at lower baseline burden. Region-specific analyses demonstrated marked, highly significant decrease in Z-scores across all regions.

CONCLUSIONS: Longitudinal Aβ-PET demonstrated substantial Aβ clearance following AAT in routine clinical practice. Aβ reduction was not significantly associated with baseline Aβ burden, ARIA, APOE-ε4 status. In adjusted analyses, greater Aβ reduction was associated with greater MMSE improvement. Our findings support Aβ-PET as a sensitive biomarker of biological treatment effect, while highlighting the complexity of linking Aβ clearance to short-term cognitive outcomes.},
}

@article {pmid42056682,
year = {2026},
author = {Song, Z and Huang, X and Jannu, AJ and Johnson, TS and Zhang, J and Huang, K},
title = {Identification of Alzheimer's disease subtypes and biomarkers from human multi-omics data using subspace merging algorithm.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {5},
pages = {e71292},
pmid = {42056682},
issn = {1552-5279},
support = {5U54AG065181//National Institutes of Health (NIH)/ ; R21AG075541//National Institutes of Health (NIH)/ ; },
mesh = {Humans ; *Alzheimer Disease/genetics/classification/pathology ; *Algorithms ; *Biomarkers ; Quantitative Trait Loci/genetics ; Male ; Female ; Brain/pathology/metabolism ; Aged ; Cohort Studies ; Genome-Wide Association Study ; Phenotype ; Transcriptome ; Multiomics ; },
abstract = {INTRODUCTION: Alzheimer's disease (AD) is a heterogeneous disease with diverse disease progression trajectories and brain pathology. Identifying AD subtypes is essential for understanding AD etiology, heterogeneity, and developing precise treatment.

METHODS: We applied a subspace-merging algorithm to integrate multi-omics data from brain tissues of three large AD cohorts and identify data-driven AD subtypes. Within each cohort, we performed multiple analyses to characterize subtype-specific biology. A Phenome-wide Association Study (PheWAS) of expression quantitative trait loci (eQTLs) targeting differentially expressed genes (DEGs) was conducted to link molecular differences to disease phenotypes.

RESULTS: We identified AD subtypes that differed in cognitive and pathological phenotypes in three cohorts. Further analyses highlighted synaptic and neurotransmission pathways, and the PheWAS revealed significant associations with disease phenotypes.

DISCUSSION: Our developed integration algorithm successfully merged different data modalities into a common subspace for patient clustering and identified data-driven subtypes. The identified transcriptomic signatures provide valuable insights into the molecular mechanisms underlying AD heterogeneity, paving the way for personalized AD treatment.},
}

Humans
*Alzheimer Disease/genetics/classification/pathology
*Algorithms
*Biomarkers
Quantitative Trait Loci/genetics
Male
Female
Brain/pathology/metabolism
Aged
Cohort Studies
Genome-Wide Association Study
Phenotype
Transcriptome
Multiomics

@article {pmid42057258,
year = {2026},
author = {Yi, Y and Jia, P and Xie, P and Peng, X and Zhu, X and Yin, S and Yan, C and Yu, G},
title = {Natural Products for Alzheimer's Disease: A New Twist Impacting Ferroptosis.},
journal = {The American journal of Chinese medicine},
volume = {},
number = {},
pages = {1-25},
doi = {10.1142/S0192415X26500266},
pmid = {42057258},
issn = {1793-6853},
abstract = {Alzheimer's disease (AD) is a neurodegenerative disorder characterized by progressive cognitive decline. Despite significant advances in AD research, effective disease-modifying therapies remain unavailable. In recent years, ferroptosis has gained increasing attention for its potential role in the pathogenesis of AD. Accumulating evidence indicates that substantial iron accumulation, dysregulation of anti-oxidant defense systems, and elevated levels of lipid peroxidation are present in the brains of AD patients. These alterations create a conducive environment for ferroptosis and are closely associated with neuronal death and cognitive dysfunction. Therefore, targeting ferroptosis-related signaling pathways holds promise as a novel strategy to delay or halt the progression of AD. Natural products, such as flavonoids, phenolic compounds, and terpenoids, have become a focus of research in the intervention of neurodegenerative diseases due to their structural diversity, broad biological activities, and relatively low toxicity. Increasing studies have demonstrated that various herbal medicines, including Rhodiola rosea, Polygala tenuifolia, Ginkgo biloba, and Poria cocos, can effectively suppress ferroptosis through multiple mechanisms. These mechanisms include scavenging free radicals, enhancing anti-oxidant capacity, modulating iron metabolism, and restoring the function of key regulators like GPX4 or system Xc[-], to thereby ameliorate AD-related neural damage. This review systematically summarizes recent advances in understanding the role of ferroptosis in AD and highlights the therapeutic potential of natural products that target ferroptotic pathways. We aim to provide theoretical support and candidate molecules for the development of novel AD treatment strategies based on ferroptosis regulation, and thus offer valuable insights for future research into new ferroptosis inhibitors.},
}

@article {pmid42057407,
year = {2026},
author = {Lee, M and Kim, M},
title = {Donepezil increases angiogenic potential in patients with Alzheimer's disease.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261444020},
doi = {10.1177/13872877261444020},
pmid = {42057407},
issn = {1875-8908},
abstract = {BackgroundAlzheimer's disease (AD) is the leading cause of dementia in the elderly. Acetylcholinesterase inhibitors are the mainstay of symptomatic treatment, and vascular dysfunction is increasingly recognized as a key contributor to AD pathophysiology. While donepezil is a standard AD treatment, its effects on the vascular system remain poorly understood despite known neurovascular interactions.ObjectiveTo investigate whether donepezil treatment influences endothelial progenitor cell (EPC) populations and differentiation capacity in patients with AD.MethodsEPCs were evaluated in healthy controls and patients with AD (n = 20 per group; N = 80 total): controls (Ctrl), patients initiating donepezil 5 mg (Dp_Start), patients receiving donepezil 5 mg for ≥6 months (Dp_5 mg), and patients escalated to 10 mg after ≥6 months of 5 mg treatment (Dp_10 mg). Peripheral blood samples were collected at baseline, 12 weeks, and 24 weeks. Circulating EPCs were quantified by flow cytometry, and EPC differentiation capacity was assessed by counting early and late EPC colony-forming units (CFUs).ResultsAt baseline, EPC differentiation capacity was reduced in AD patients compared with controls. Circulating EPC levels did not show significant changes across groups or treatment durations. In contrast, both early and late EPC CFU counts were significantly increased in AD patients receiving donepezil, particularly during the first 12 weeks of treatment. This effect was pronounced in patients initiating donepezil therapy.ConclusionsDonepezil enhanced EPC differentiation into early and late populations without altering circulating EPC levels. These findings suggest that donepezil improves EPC functional competence and vascular regenerative capacity beyond its established cognitive effects.},
}

@article {pmid42057743,
year = {2026},
author = {Radhakrishnan, A and Dutta, D and Saha, M and Venkatakrishnan, S and Kulkarni, A and Chandrachari, KP and Salins, PC and Suresh, A},
title = {Neuro-reparative potential of hyperbaric oxygen therapy in animal models of Alzheimer's and Parkinson's diseases: systematic review and meta-analysis.},
journal = {Neurodegenerative disease management},
volume = {},
number = {},
pages = {1-9},
doi = {10.1080/17582024.2026.2665357},
pmid = {42057743},
issn = {1758-2032},
abstract = {INTRODUCTION: This systematic review and meta-analysis explored the efficacy of Hyperbaric oxygen therapy (HBOT) in preclinical models of Alzheimer's disease (AD) and Parkinson's disease (PD).

METHODS: Data were extracted as per PRISMA guidelines using specific search criteria, with bias assessed using SYRCLE guidelines. Random-effect models were used for meta-analyses of key outcomes, and forest plots were generated. Outcomes assessed included cognitive and motor performance, neuroinflammation, oxidative stress, mitochondrial function, apoptosis, and dopaminergic neuron survival.

RESULTS: The PRISMA search yielded 8 studies (AD: 3; PD: 5) from a total of 8261 articles identified. A total of 308 animals were reported across the studies; however, 182 were included in the meta-analysis, as only animals from relevant treatment and corresponding control groups with extractable outcome data were eligible for quantitative analysis. HBOT significantly improved cognitive function (reduced escape latency, Standardized Mean Difference; SMD: -2.13), improved spatial memory, and reduced compensatory locomotor activity (decreased distance traveled, SMD: -6.94). The markers of neuroinflammation (lower TNF-α, higher IL-10), oxidative stress (SOD, MDA), mitochondrial biogenesis (SIRT1, PGC-1α, TFAM, VDAC), and anti-apoptotic markers (higher Bcl-xl, lower Bax) showed differences in post-HBO treatment. HBOT also preserved dopaminergic neurons in PD models.

CONCLUSIONS: These preclinical findings support HBOT as a potential complementary neuroprotective therapy for AD and PD, warranting further clinical validation.},
}

@article {pmid41794773,
year = {2026},
author = {Soliman, AR and Fahmy, E and Mahmoud Ahmed, R},
title = {The obesity-brain axis: a comprehensive review of neurological complications and therapeutic interventions in metabolic syndrome.},
journal = {Diabetology & metabolic syndrome},
volume = {18},
number = {1},
pages = {},
pmid = {41794773},
issn = {1758-5996},
abstract = {BACKGROUND: Obesity has emerged as a major global health issue, affecting multiple organ systems. Within the central nervous system obesity causes a series of disruptions that can significantly affect neurological function. Identifying obesity as a modifiable risk factor presents opportunities for preventive and therapeutic strategies that may significantly diminish neurological sequelae.

OBJECTIVE: This narrative review aims to summarize current evidence on how obesity contributes to different neurological diseases and focusing on biological mechanisms linking obesity to these conditions, outlines the characteristic clinical presentations of obesity-related neurological diseases across different age groups and potential therapeutic strategies.

METHODS: This narrative review integrates findings from comprehensive search of PubMed, EMBASE, and Cochrane Library to investigate how obesity and metabolic syndrome relate to a broad spectrum of neurological disorders. After screening 1,950 records, 48 studies were included supplemented by nine manually identified articles.

RESULTS: Obesity triggers a range of biological changes in the nervous system such as increased oxidative stress, persistent low‑grade inflammation, disruption of the blood–brain barrier, and impaired mitochondrial function. Together, these changes raise the risk of several neurological problems, including cognitive decline, Alzheimer’s disease, stroke, faster progression of multiple sclerosis, greater epilepsy‑related complications, transformation of episodic into chronic migraine, idiopathic intracranial hypertension, and various peripheral neuropathies. The impact of body mass index on neurological health differs across diseases and age groups with obesity in midlife representing a high risk. Lifestyle‑based strategies especially Mediterranean or ketogenic dietary patterns, regular physical activity and weight reduction show encouraging potential in reducing these neurological risks.

CONCLUSIONS: Obesity is a modifiable contributor to many neurological disorders. Identifying at‑risk individuals early and adopting healthier daily habits, following tailored diets and managing weight effectively may help lessen the neurological consequences of obesity. Continued research is essential to clarify underlying mechanisms and refine treatment strategies for different patient groups.},
}

@article {pmid41851792,
year = {2026},
author = {Zhang, JW and Li, R and Niu, YX and Liu, SY and Li, CH and Hao, XD and Wang, SH and Chen, S and Wang, FY},
title = {Clinical, neuroimaging, and biomarker profiling of four Alzheimer's disease pedigrees caused by pathogenic APP variants.},
journal = {Alzheimer's research & therapy},
volume = {18},
number = {1},
pages = {},
pmid = {41851792},
issn = {1758-9193},
support = {82171196//the National Natural Science Foundation of China/ ; 241111313500//the Key Research and Development Program of Henan Province/ ; SBGJ202402012//the Medical Science and Technology Research Project of Henan Province/ ; },
abstract = {BACKGROUND: Current understanding of the fluid biomarker profile in early-onset Alzheimer’s disease (EOAD) associated with pathogenic APP variants remains limited. We characterized four EOAD pedigrees carrying pathogenic APP variants using clinical, neuroimaging, and biofluid biomarkers, comparing them with contemporaneous sporadic AD (SAD) to inform early detection.

METHODS: Between December 2022 and December 2024, we enrolled 206 individuals from four APP-associated families harboring the D678G, V717I, or M722K variants; 92 individuals underwent genetic testing. Based on genotype and clinical status, participants were classified into three groups: symptomatic APP variant carriers (SMC; n = 11), asymptomatic APP variant carriers (AMC; n = 19), and cognitively normal non-carriers (NC; n = 62). In addition, 60 patients with sporadic Alzheimer’s disease and an age at onset of ≤ 65 years (SAD; sporadic EOAD) were included as a comparison group for fluid biomarker analyses. All participants included in the plasma analyses underwent clinical assessments, and plasma levels of P-tau217, P-tau181, Aβ42, Aβ40, GFAP, NfL, and the Aβ42/Aβ40 ratio were quantified. Structural MRI, PET, and cerebrospinal fluid biomarkers were obtained in a subset of participants, where available. Group comparisons were performed using the Kruskal-Wallis and Mann-Whitney U tests, with false discovery rate adjustment for multiple comparisons using the Benjamini-Hochberg procedure (P_FDR). Additionally, two patients treated with lecanemab underwent longitudinal follow-up during the first 15 infusions.

RESULTS: Based on family informant reports and clinical observations, the median age at onset (AAO) among affected individuals in these pedigrees was 48.50 (44.0, 51.8) years. Plasma biomarker analyses showed that P-tau181, P-tau217, and GFAP levels were significantly higher in the SMC and SAD groups than in the AMC and NC groups (P_FDR < 0.05). Compared with the SMC group, the SAD group exhibited higher Aβ40 levels and a lower Aβ42/Aβ40 ratio (P_FDR < 0.05). Among V717I carriers, multiple biomarkers differed significantly between SMC and AMC (P_FDR < 0.05), whereas no significant differences were detected in the D678G or M722K subgroups. In addition, given the current sample size, APOE ε4 status was not associated with additional modification of plasma biomarker levels or AAO. No amyloid-related imaging abnormalities (ARIA) were observed during the lecanemab treatment period. From the pre-infusion baseline to immediately before the 15th infusion, one patient showed decreases in P-tau181 (− 5.70%), P-tau217 (− 12.23%), and GFAP (− 42.93%), accompanied by a mild improvement in cognitive performance; the other patient showed a reduction in P-tau181 (− 28.30%) but increases in GFAP (+ 36.59%) and NfL (+ 174.01%), with overall stable cognition.

CONCLUSIONS: Plasma biomarkers provide critical evidence to advance our understanding of APP variant-associated EOAD. Both APP variant-associated EOAD and sporadic EOAD showed a similar biomarker profile, with higher plasma P-tau181, P-tau217, and GFAP levels than those in AMC and NC. In contrast, the two groups exhibited divergent patterns in Aβ40 levels and the Aβ42/Aβ40 ratio. In addition, given the current sample size, APOE ε4 status was not found to have an additional modifying effect on plasma biomarkers among APP variant carriers.

SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13195-026-02016-5.},
}

@article {pmid41851829,
year = {2026},
author = {Gupta, A and Thirugnanam, K and Bice, Z and Lowman, AK and Rarick, KR and LaViolette, PS and Pan, A and Franczak, M and Ramchandran, R},
title = {Ciliary p75 neurotrophin receptor (p75NTR) facilitates the enrichment of exogenous amyloid beta (Aβ 1-42) peptide and promotes oxidative stress in human hippocampal astrocytes.},
journal = {BMC molecular and cell biology},
volume = {27},
number = {1},
pages = {},
pmid = {41851829},
issn = {2661-8850},
support = {R33HL154254 and R01HL179583/NH/NIH HHS/United States ; NA//Brain 5K Run/ ; NA//Ryan M. Schaller Foundation/ ; R33HL154254 and R01HL179583/NH/NIH HHS/United States ; },
abstract = {UNLABELLED: Accumulation of amyloid beta 1–42 (Aβ42) peptide in the extracellular space in the brain is a major observation in Alzheimer’s Disease (AD)-related pathology. Astrocytes are known to play pivotal role in clearing the extracellular aβ peptide from the brain, and the underlying mechanism of Aβ42 peptide clearance remains underappreciated. Like other cell types in the brain, astrocytes have primary cilia, a nonmotile microtubule-based organelle. Aβ42 peptide is reported to affect cilia length or structure in multiple cell types including neurons and inhibit ciliary p75 neurotrophin receptor (p75NTR). To date, the relationship between the extracellular Aβ42 and the astrocytic cilia has not been established. In this work, using primary human hippocampal astrocytes and post-mortem brain specimens obtained from AD patients, we performed molecular, flow cytometry and imaging approaches to investigate the relationship of astrocytic cilia and extracellular Aβ42 peptide. Our data demonstrate that the exogenous Aβ42 peptide treatment in vitro, induces expression of p75NTR in astrocyte cilia in a dose-dependent fashion. We also observed the enrichment of exogenous Aβ42 peptide in the astrocyte cilia and the plasma membrane of astrocytes. In exogenous Aβ42 peptide-treated groups, we observed aberrant proliferation and cell cycle, increased oxidative stress and apoptosis. Interestingly, we observed an enrichment of astrocytic p75NTR expression in the human post-mortem AD-brain. Silencing RNA (siRNA)-mediated knockdown of p75NTR gene significantly minimized the enrichment of exogenous Aβ peptide and the oxidative stress in primary hippocampal astrocytes in vitro. These studies unravel a molecular signaling mechanism that involves Aβ42 peptide-induced p75NTR-mediated oxidative stress that affects overall astrocyte health in AD-associated pathology.

SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12860-026-00581-z.},
}

@article {pmid41857623,
year = {2026},
author = {Agosta, F and Cecchetti, G and Spinelli, EG and Ghirelli, A and Rugarli, G and Pisano, S and Coraglia, F and Canu, E and Castelnovo, V and Sibilla, E and Gilioli, A and Tripodi, C and Freri, F and Bianchi, A and Vezzulli, P and Calloni, S and Falini, A and Samanes Gajate, AM and Panzacchi, A and Pepe, G and Ferri, C and Chiti, A and Filippi, M},
title = {Real-world implementation of lecanemab and donanemab in an Italian memory center: a 1-year experience.},
journal = {Alzheimer's research & therapy},
volume = {18},
number = {1},
pages = {},
pmid = {41857623},
issn = {1758-9193},
abstract = {BACKGROUND: Anti-amyloid monoclonal antibodies are entering clinical practice for early symptomatic Alzheimer’s disease (AD), but European real-world data on feasibility, safety, and biomarker monitoring remain limited. We report the first year of implementation of lecanemab and donanemab in an Italian tertiary memory center.

METHODS: We conducted a prospective observational real-world cohort study at the Center for Alzheimer’s and Related Diseases of IRCCS Ospedale San Raffaele (Milan, Italy). Twenty-nine treatment courses were administered in patients with early symptomatic AD (lecanemab, n = 9; donanemab, n = 20) under European Medicines Agency–aligned safety monitoring and risk-mitigation protocols. Given the unbalanced treatment groups, results are descriptive and not intended for direct comparison between treatments. Safety surveillance included serial magnetic resonance imaging for amyloid-related imaging abnormalities (ARIA) and systematic recording of infusion-related reactions. Biological monitoring included amyloid positron emission tomography with Centiloid quantification and plasma biomarkers (phosphorylated tau 181 and 217, glial fibrillary acidic protein, neurofilament light chain, and amyloid-β 42/40 ratio) at baseline and follow-up. Baseline comparisons and longitudinal changes were assessed using appropriate parametric or nonparametric statistical methods.

RESULTS: ARIA were infrequent. In donanemab-treated patients, mildly symptomatic ARIA-E occurred in 10% (2/20) and asymptomatic ARIA-H in 15% (3/20). In lecanemab-treated patients, asymptomatic ARIA-H occurred in 11% (1/9). Infusion-related reactions occurred in 21% (6/29) of treatment courses and were manageable with standardized premedication. Among 11 patients with six-month follow-up, amyloid burden decreased significantly (mean change − 52.4 Centiloids), and 75% of donanemab-treated patients (6/8) and 0% of lecanemab-treated patients reached amyloid positron emission tomography negativity (< 11CL). Plasma phosphorylated tau 181 and glial fibrillary acidic protein showed directional declines, consistent with expected biomarker trajectories under anti-amyloid therapy, while cognitive measures showed no significant change.

CONCLUSIONS: In a structured multidisciplinary framework, lecanemab and donanemab were feasibly implemented with a preliminary favorable early safety profile, substantial amyloid reduction, and measurable plasma biomarker changes in routine practice. This experience supports the feasibility of structured real-world pathways for deployment and monitoring of disease-modifying therapies in European memory clinics, within the limitations of a small cohort and short follow-up.},
}

@article {pmid42047940,
year = {2026},
author = {He, DL and Wu, Z and Jia, RJ and Wu, TY and Qiu, YM and Fan, YG},
title = {AS1842856 Reduces β-Amyloid Burden via Inhibiting PLA2G4A-Mediated Lysosomal Dysfunction in APP/PS1 Mice.},
journal = {CNS neuroscience & therapeutics},
volume = {32},
number = {4},
pages = {e70910},
pmid = {42047940},
issn = {1755-5949},
support = {82301626//National Natural Science Foundation of China/ ; },
mesh = {Animals ; *Lysosomes/drug effects/metabolism ; Mice, Transgenic ; Amyloid beta-Protein Precursor/genetics ; Mice ; *Group IV Phospholipases A2/metabolism/antagonists & inhibitors ; *Amyloid beta-Peptides/metabolism ; Presenilin-1/genetics ; *Alzheimer Disease/drug therapy/metabolism/genetics/pathology ; Disease Models, Animal ; Male ; Humans ; Mice, Inbred C57BL ; Cell Line, Tumor ; },
abstract = {AIMS: Both cytosolic phospholipase A2 (PLA2G4A)-induced lysosomal membrane disruption and glycogen synthase kinase-3α/β (GSK3α/β)-mediated lysosomal dysfunction have been implicated in neurodegeneration, with a potential regulatory relationship between these two pathways. We recently identified AS1842856 (AS) as a suppressor of GSK3α/β. This study was therefore designed to investigate whether AS mitigates Alzheimer's disease (AD) progression by targeting PLA2G4A to restore lysosomal homeostasis.

METHODS: The therapeutic potential of AS was investigated in APP/PS1 mice by analyzing cognitive function, β-amyloid (Aβ) load, and lysosomal integrity, with its mechanism of action further explored in N2a-sw cells.

RESULTS: AS treatment reduced GSK3α/β expression in both APP/PS1 mice and N2a-sw cells. This suppression led to decreased PLA2G4A levels, restoration of lysosomal membrane integrity, and enhanced lysosomal degradation of Aβ. Consequently, AS administration alleviated Aβ burden and improved cognitive function in APP/PS1 mice. Moreover, AS was found to inhibit NF-κB-mediated PLA2G4A expression. Knockdown experiments further revealed that reduced GSK3β-but not GSK3α-reproduced the suppressive effect on PLA2G4A.

CONCLUSION: Our study identified the GSK3β/NF-κB/PLA2G4A signaling axis as a novel therapeutic target in AD, and AS could inhibit this axis to mitigate Aβ pathology by promoting lysosomal degradation of Aβ.},
}

Animals
*Lysosomes/drug effects/metabolism
Mice, Transgenic
Amyloid beta-Protein Precursor/genetics
Mice
*Group IV Phospholipases A2/metabolism/antagonists & inhibitors
*Amyloid beta-Peptides/metabolism
Presenilin-1/genetics
*Alzheimer Disease/drug therapy/metabolism/genetics/pathology
Disease Models, Animal
Male
Humans
Mice, Inbred C57BL
Cell Line, Tumor

@article {pmid42049507,
year = {2026},
author = {Morello, CM and Mnatzaganian, CL and Painter, NA},
title = {Emerging and Off-Label Uses Of Glucagon-Like Peptide-1 Receptor Agonists (GLP1-RA) and Dual GIP/GLP1-RAs.},
journal = {Journal of the American Board of Family Medicine : JABFM},
volume = {39},
number = {1},
pages = {},
doi = {10.3122/jabfm.2025.250158R1},
pmid = {42049507},
issn = {1558-7118},
mesh = {Humans ; *Glucagon-Like Peptide-1 Receptor Agonists ; *Diabetes Mellitus, Type 2/drug therapy ; *Off-Label Use ; *Obesity/drug therapy ; *Gastric Inhibitory Polypeptide/therapeutic use ; *Hypoglycemic Agents/therapeutic use ; },
abstract = {BACKGROUND: Glucagon-like peptide-1 receptor agonists (GLP1-RAs) and the glucagon-dependent insulinotropic polypeptide (GIP)/GLP1-RA are approved for type 2 diabetes (T2D) and obesity given their profound impact on glycemic weight management. Additional indications include reducing cardiovascular disease risk and progression of chronic kidney disease (CKD) in T2D as well as obstructive sleep apnea in patients with obesity. These enhanced effects are likely due to their pleiotropic effects, leading to decreased inflammation and other benefits. This review explored emerging evidence for uses of GLP1-RAs and GIP/GLP1-RA that have been researched but not yet approved. Clinicians may use this information to guide treatment decisions.

REVIEW PROCESS: PubMed and Embase literature searches were conducted using Medical Subject Heading terms. Studies referencing GLP1-RAs and GIP/GLP1-RA were included if they were published in approximately the last decade, included adults, and were either a randomized controlled trial, meta-analysis, or observational study. Of 319 articles reviewed, 27 met inclusion criteria.

EMERGING AND COMPELLING USES: Initial positive impacts have been noted for the following conditions: liver disease/liver transplant, CKD/kidney transplant, Alzheimer's disease, Parkinson's disease, substance use disorders, osteoarthritis, rheumatoid arthritis, psoriasis, COVID-19 virus, asthma, chronic obstructive pulmonary disorder, polycystic ovarian syndrome, and short bowel syndrome.

CONSIDERATIONS: Large randomized controlled trials may lead to approvals of these conditions and are encouraged. Safety and adverse effects of these medications must be assessed when initiating or modifying doses.

CONCLUSION: GLP1-RAs and GIP/GLP1-RA have demonstrated early benefits to several conditions beyond their current approved indications. Clinicians can use this information to determine treatment options for patients, particularly in those with T2D, cardiovascular disease, and/or obesity.},
}

Humans
*Glucagon-Like Peptide-1 Receptor Agonists
*Diabetes Mellitus, Type 2/drug therapy
*Off-Label Use
*Obesity/drug therapy
*Gastric Inhibitory Polypeptide/therapeutic use
*Hypoglycemic Agents/therapeutic use

@article {pmid42051019,
year = {2026},
author = {Hacımüftüoğlu, A and Saraçoğlu, N and Saffour, S and Abad, N and Kesgun, Y and Zegheb, N and Gundeger, E and Yeşilyurt, F and Ateş, MN and Bati-Ayaz, G and Altunlu, Ö and Çınar, B and Yörük, MA and Okkay, U and Özkaraca, M and Ateş, O and Taghizadehghalehjoughi, A and Lafzi, F and Türkez, H},
title = {Multi-Target Neuroprotective Compound Exhibits EAAT2-Modulating and Alzheimer's Pathology-Attenuating Effects in In Vitro and In Vivo Models.},
journal = {ACS chemical neuroscience},
volume = {},
number = {},
pages = {},
doi = {10.1021/acschemneuro.5c00873},
pmid = {42051019},
issn = {1948-7193},
abstract = {Alzheimer's disease (AD) is a debilitating neurodegenerative disorder characterized by cognitive decline and memory loss. Current treatments offer limited efficacy, necessitating the development of innovative multitarget therapeutic strategies. Here, we present N[3],N[5]-bis(2-(5-methoxy-1H-indol-3-yl)ethyl)-2,6-dimethyl-4-(2-nitrophenyl)pyridine-3,5-dicarboxamide (HCM-01), a novel compound developed to target multiple neurodegenerative pathways implicated in AD. In vitro assays included MTT-based cell viability analyses performed in two complementary experimental settings: primary neuronal cultures and astrocyte-based in vitro cell culture models exposed to glutamate. In primary hippocampal neuronal cultures, glutamate exposure induced a statistically significant reduction in cell viability compared with vehicle-treated controls, consistent with glutamate-induced excitotoxicity. Under these conditions, HCM-01 treatment resulted in a statistically significant improvement in neuronal viability, showing a greater protective effect compared with donepezil and memantine. In contrast, in astrocyte-based in vitro cultures, the applied glutamate concentration did not induce overt cytotoxicity, in line with the intrinsic neuroprotective and glutamate-buffering role of astrocytes. Accordingly, astrocytic experiments were designed to assess functional modulation of glutamate-handling mechanisms rather than cell survival. Western blot analysis in C8-D1A astrocytic cells demonstrated increased expression of excitatory amino acid transporter 2 (EAAT2) following HCM-01 treatment compared with control and reference drug-treated groups, suggesting modulation of astrocyte-mediated glutamate homeostasis. In parallel, redox analyses revealed that HCM-01 improved oxidative/antioxidative balance, as evidenced by increased total antioxidant capacity (TAC) and reduced total oxidant status (TOS), supporting an indirect antioxidant contribution to its functional effects. In vivo behavioral assessment of HCM-01 in a streptozotocin (STZ)-induced Alzheimer's model in female Sprague-Dawley rats demonstrated that administration of HCM-01 at doses of 50 mg/kg orally (oral, P.O. and intraperitoneal, I.P.) and 100 mg/kg (P.O.), significantly improved cognitive and memory functions in the passive avoidance (PA), Morris water maze (MWM), and locomotor activity tests. Moreover, histopathological and immunohistochemical analyses of different hippocampal regions revealed reduced neuronal damage, attenuation of tau pathology, antiamyloidogenic effect, and restoration of cholinergic function. Complementary in silico studies, including molecular docking, molecular dynamics simulations (MDS), and free energy calculations, suggested potential interactions of HCM-01 with the allosteric site of EAAT2. Taken together, these findings suggest that HCM-01 exerts neuroprotective effects against glutamate-induced excitotoxicity in primary hippocampal neurons while additionally modulating glutamatergic homeostasis and redox balance through functional mechanisms in astrocyte-based models, supporting its relevance as a multitarget preclinical candidate for early stage AD mechanisms.},
}

@article {pmid42051092,
year = {2026},
author = {Sun, Y and Chan, TW and Liao, W and Li, M and Mao, X and Feng, Y and Rong, J and Zhao, J},
title = {In Silico Design and Evaluation of Diosmin Analogs for Targeting Peroxisome Proliferator-activated Receptor γ (PPAR-γ) Against Alzheimer's Disease.},
journal = {Current neuropharmacology},
volume = {},
number = {},
pages = {},
doi = {10.2174/011570159X453424260218065734},
pmid = {42051092},
issn = {1875-6190},
abstract = {Alzheimer's disease (AD) is a neurodegenerative disorder characterized by progressively declining cognitive abilities and memory impairment. This disease increasingly challenges the quality of life and health of the elderly population, underscoring the need for effective therapeutic strategies. The existing anti-AD medications are designed to improve symptoms but not to cure the disease. Novel drugs are urgently needed to target the specific mechanisms that mediate disease progression. Peroxisome proliferator-activated receptor gamma (PPAR-γ) is a potential target for the development of anti-AD therapies. Through virtual screening of natural PPAR-γ ligands, the flavonoid diosmin was found to bind to PPAR-γ with high potency. This study exploited diosmin as a lead compound to design a panel of diosmin analogs via chemical modifications for better biological efficacy in targeting PPAR-γ. These diosmin analogs were evaluated using in silico approaches, including molecular docking, absorption, distribution, metabolism, and excretion (ADME) predictions, and molecular dynamics (MD) simulations. As a result, molecular docking identified 12 di-osmin analogs with better binding affinity to PPAR-γ compared with diosmin. ADME and MD analyses demonstrated that S1DhP1 exhibited lower binding free energy, better water solubility, and stability than diosmin. Thus, this study provides important information via in silico approaches and hypotheses, suggesting S1DhP1 as a promising PPAR-γ agonist for the treatment of AD that warrants further experimental validation.},
}

@article {pmid42051629,
year = {2026},
author = {Cullins, MJ and Converse, AK and Rowe, LM and Hoerst, AG and Hibbard, WK and Russell, JA and Connor, NP and Ciucci, MR},
title = {Oropharyngeal dysphagia and amyloid beta pathology in the TgF344-AD rat model of Alzheimer's disease.},
journal = {Frontiers in behavioral neuroscience},
volume = {20},
number = {},
pages = {1812480},
pmid = {42051629},
issn = {1662-5153},
abstract = {INTRODUCTION: Dysphagia is a major consequence of Alzheimer's disease (AD) that is understudied and undertreated. Neuropathology in AD occurs early in the disease progression, but little is known about pathologies underlying functional swallowing changes; this knowledge gap is a barrier to developing effective treatment. We hypothesized that an established AD rat model (TgF344-AD) would demonstrate significant deficits in oromotor/swallowing function versus Wild Type (WT) with corresponding amyloid beta pathology in brain structures critical to swallowing.

METHODS: Nine male TgF344-AD and 6 Wildtype Fisher 344 rats underwent deglutition assessments and PET imaging using the radiotracer [[11]C]PiB to assess brain and brainstem amyloid beta (Aβ) pathology at 11 months of age-a time point corresponding to early-middle stage AD progression. A priori brain regions of interest (ROIs) included those commonly associated with Aβ pathology and more specific swallowing associated structures such as brainstem nuclei and cortical motor areas. Deglutition was assessed using a videofluoroscopic swallow study and a pasta biting task.

RESULTS: Significantly increased levels of Aβ in the AD group were found in regions critical to swallowing motor control including the secondary motor area, thalamus, nucleus ambiguus, and hypoglossal nuclei. The AD group demonstrated significant changes in aerodigestive coordination, including delayed swallow onset, increased apnea duration, and increased frequency of aberrant post-swallow inhale pattern that was correlated with nucleus ambiguus Aβ levels. The AD group also exhibited altered oral processing including reduced bolus size and mastication rate.

CONCLUSION: The TgF344-AD rat model of Alzheimer's exhibits robust changes in oral processing and respiratory-swallow coordination that parallel clinical AD dysphagia. At this early-middle stage timepoint, Aβ pathology is primarily impacting cerebral swallowing networks as well as the nucleus ambiguus and hypoglossal nuclei in the brainstem. Our finding of increased Aβ in the nucleus ambiguus warrants further study as this motor nucleus plays a role in swallowing, respiration, and vocalization-all factors that are known to be impacted by AD in the clinical population.},
}

@article {pmid42052145,
year = {2026},
author = {Tariot, PN and Chumki, SR and Wang, D and Such, P and Palma, AM and Zhang, Z and Montano, CB},
title = {Brexpiprazole for Agitation in Patients with Alzheimer's Dementia with and without Co-Occurring Psychosis: Post Hoc Analysis of Short- and Long-Term Trials.},
journal = {Neuropsychiatric disease and treatment},
volume = {22},
number = {},
pages = {586701},
pmid = {42052145},
issn = {1176-6328},
abstract = {PURPOSE: Patients with Alzheimer's dementia may experience co-occurring agitation and psychosis symptoms. This exploratory post hoc analysis aimed to analyze the efficacy and safety of brexpiprazole for agitation in patients with Alzheimer's dementia with and without co-occurring psychosis.

PARTICIPANTS AND METHODS: Data were pooled from two Phase 3, 12-week, randomized, double-blind, placebo-controlled, fixed-dose trials of brexpiprazole versus placebo in participants with Alzheimer's dementia and agitation, conducted in Europe, Russia, and the US (ClinicalTrials.gov identifiers: NCT01862640, NCT03548584). Post hoc, participants were stratified into subgroups with or without co-occurring psychosis at baseline, defined as a score ≥4 on the Neuropsychiatric Inventory Delusions domain, Hallucinations domain, or both. Efficacy was assessed by the Cohen-Mansfield Agitation Inventory Total score. Safety was assessed by treatment-emergent adverse events (TEAEs).

RESULTS: 142/607 participants (23.4%) had co-occurring psychosis at baseline. Brexpiprazole 2 or 3 mg/day was associated with greater improvement in agitation compared with placebo in participants with co-occurring psychosis (least squares mean difference at Week 12, -9.18 [95% confidence interval -15.2 to -3.12]; P=0.004; Cohen's d=0.52) and in participants without co-occurring psychosis (-4.22 [-6.91 to -1.54]; P=0.002; Cohen's d=0.29). In participants with co-occurring psychosis, for brexpiprazole and placebo respectively, 52.9% and 40.0% had TEAEs, and 3.4% and 9.1% discontinued due to TEAEs. No deaths occurred among participants with co-occurring psychosis. In participants without co-occurring psychosis, for brexpiprazole and placebo respectively, 49.3% and 38.2% had TEAEs, and 5.5% and 2.6% discontinued due to TEAEs. Two participants without co-occurring psychosis died; neither death was considered related to brexpiprazole treatment.

CONCLUSION: In this post hoc analysis, brexpiprazole improved agitation and was generally well tolerated in patients with Alzheimer's dementia with and without co-occurring psychosis. These exploratory data suggest that brexpiprazole may be of value to patients with Alzheimer's dementia who present with agitation and psychosis in clinical practice.},
}

@article {pmid42052655,
year = {2026},
author = {Zhao, R and Guo, M and Yang, F and Yan, Y and Tian, D and Deng, L and Wang, Q and Xie, M},
title = {A microglia membrane biomimetic platinum-based MOF-loaded quercetin nanodrug delivery system for the treatment of Alzheimer's disease.},
journal = {Journal of materials chemistry. B},
volume = {},
number = {},
pages = {},
doi = {10.1039/d6tb00201c},
pmid = {42052655},
issn = {2050-7518},
abstract = {The aberrant deposition of β-amyloid (Aβ) is a central pathological hallmark of Alzheimer's disease (AD), triggering oxidative stress, metal ion dyshomeostasis, and excessive microglial activation in a self-perpetuating pathological cascade. To address these interconnected processes, a platinum-based metal-organic framework (Pt-MOF) with intrinsic antioxidant enzyme-mimetic activity was constructed and loaded with quercetin (Qu) to regulate microglial dysfunction. To enhance blood-brain barrier (BBB) penetration and inflammation-targeting capability, Pt-MOF/Qu was further camouflaged with microglial cell membranes (BV2), yielding Pt-MOF/Qu/BV2 nanoparticles. In vitro studies demonstrated that Pt-MOF/Qu/BV2 efficiently scavenged reactive oxygen species and effectively chelated Cu[2+] ions via surface functional groups, thereby inhibiting Aβ aggregation and promoting the disassembly of preformed Aβ aggregates. In addition, the Pt-MOF enabled efficient loading and controlled release of Qu, which significantly restored mitochondrial membrane potential and alleviated microglial over-activation. The BV2 membrane coating markedly improved the biocompatibility and BBB translocation efficiency of the nanoplatform. Furthermore, Pt-MOF/Qu/BV2 significantly reduced reactive oxygen species (ROS) in vivo and Aβ brain plaque accumulation in the head region, alleviated neurotoxicity and improved the behavioral phenotype in the C. elegans AD model. Overall, this biomimetic multifunctional MOF-based nanoplatform represents a promising multi-target therapeutic strategy for AD.},
}

@article {pmid42052761,
year = {2026},
author = {Guo, Y and Zhang, Z and Chen, B and Liu, H and Wei, F and Liu, X and Guo, Z},
title = {Functional Connectivity Alterations in the Cholinergic Neural Circuits of Patients With Alzheimer's Disease: A Donepezil Intervention Study Using Resting-State Functional Magnetic Resonance Imaging.},
journal = {Journal of integrative neuroscience},
volume = {25},
number = {4},
pages = {50039},
doi = {10.31083/JIN50039},
pmid = {42052761},
issn = {0219-6352},
support = {2017KY109//General Project of the Department of Science and Technology of Zhejiang Province/ ; 2020358406//General Project of the Department of Science and Technology of Zhejiang Province/ ; 2018KY031//General Project of the Department of Science and Technology of Zhejiang Province/ ; 2024KY873//General Project of the Department of Science and Technology of Zhejiang Province/ ; [2024]90662//National Leading Medical Specialty Development Project-Department of Geriatrics, Tongde Hospital of Zhejiang Province/ ; [2024]10//Zhejiang Provincial Alliance of Traditional Chinese Medicine Advantage Specialty for Geriatric Diseases/ ; },
mesh = {Humans ; *Donepezil/pharmacology/administration & dosage ; *Alzheimer Disease/drug therapy/diagnostic imaging/physiopathology ; Male ; Female ; Magnetic Resonance Imaging ; Aged ; *Cholinesterase Inhibitors/pharmacology/administration & dosage ; *Nerve Net/diagnostic imaging/drug effects/physiopathology ; Middle Aged ; *Connectome ; *Basal Forebrain/diagnostic imaging/drug effects/physiopathology ; Longitudinal Studies ; *Nootropic Agents/pharmacology/administration & dosage ; Cerebellum/diagnostic imaging/physiopathology/drug effects ; Aged, 80 and over ; },
abstract = {BACKGROUND: Although donepezil alleviates Alzheimer's disease (AD) symptoms by raising acetylcholine levels, its impact on cholinergic pathways remains unclear. In this longitudinal, resting-state functional magnetic resonance imaging (rs-fMRI) study, we investigated donepezil-induced changes in cholinergic pathway networks in AD.

METHODS: AD patients and healthy controls (HCs) were enrolled. AD patients received 24 weeks of donepezil treatment. Cognitive and emotional symptoms were assessed using the Mini-Mental State Examination (MMSE), Cornell Scale for Depression in Dementia (CSDD), and Neuropsychiatric Inventory (NPI) pre- and post-treatment. rs-fMRI was used to examine basal forebrain (BF) functional connectivity.

RESULTS: Sixteen AD patients and 16 HCs completed the study. Post-treatment MMSE scores improved, and NPI and CSDD scores decreased. Reduced BF functional connectivity in the left cerebellar lobule VI, post-treatment, was revealed by rs-fMRI. Compared with HCs, post-treatment AD patients showed lower BF functional connectivity in the right postcentral gyrus (PoG); pre-treatment patients exhibited higher BF functional connectivity in the left cerebellar lobule VI. Right PoG functional connectivity was negatively correlated with disease duration pre-treatment and positively correlated with MMSE post-treatment.

CONCLUSIONS: Donepezil improved clinical symptoms in AD by modulating the BF-PoG cholinergic pathway.},
}

Humans
*Donepezil/pharmacology/administration & dosage
*Alzheimer Disease/drug therapy/diagnostic imaging/physiopathology
Male
Female
Magnetic Resonance Imaging
Aged
*Cholinesterase Inhibitors/pharmacology/administration & dosage
*Nerve Net/diagnostic imaging/drug effects/physiopathology
Middle Aged
*Connectome
*Basal Forebrain/diagnostic imaging/drug effects/physiopathology
Longitudinal Studies
*Nootropic Agents/pharmacology/administration & dosage
Cerebellum/diagnostic imaging/physiopathology/drug effects
Aged, 80 and over

@article {pmid42052762,
year = {2026},
author = {Balakrishnan, J and Kannan, S and Shanmugam, K and Sugasini, D},
title = {Targeting Lipid Metabolism in Alzheimer's Disease: Emerging Insights and Future Directions.},
journal = {Journal of integrative neuroscience},
volume = {25},
number = {4},
pages = {48436},
doi = {10.31083/JIN48436},
pmid = {42052762},
issn = {0219-6352},
mesh = {Humans ; *Alzheimer Disease/metabolism/genetics/drug therapy ; *Lipid Metabolism/physiology ; Animals ; Lipidomics ; },
abstract = {Alzheimer's disease (AD) is a multifactorial neurodegenerative disease that is conventionally characterized by amyloid-β and tau pathology. There is growing evidence, however, that lipid metabolic disturbances are part of the biology of the disease, and not a secondary phenomenon. Lipid signaling controls membrane organization, amyloid precursor protein, tau phosphorylation, mitochondrial energetics, neuroinflammatory signaling, and synaptic stability. The accumulating genetic evidence, including risk variants in the APOE (apolipoprotein E), ABCA1 (ATP-binding cassette subfamily A member 1), ABCA7 (ATP-binding cassette subfamily A member 7), and TREM2 (Triggering receptor expressed on myeloid cells 2) genes, further makes lipid transport and lipid-sensing pathways central to late-onset AD vulnerability. Recent developments in lipidomics based on mass spectrometry have revealed concerted changes in phospholipids, sphingolipids, sterols, and oxidized lipid derivatives in brain tissue and peripheral biofluids. Instead of single abnormalities, directional metabolic imbalance is indicated by pathway changes, including decreased sphingomyelin-to-ceramide ratios and decreased polyunsaturated phospholipids. Co-analysis of lipidomic, genomic, and proteomic data has shown the existence of metabolically different subgroups, which aids genotype stratified risk evaluation and the lipid responder phenotype concept. Protein-centered therapies are complemented by therapeutic strategies that focus on lipid homeostasis, such as the regulation of cholesterol efflux, sphingolipid metabolism, pro-resolving lipid mediators, and metabolic reprogramming. There is also emerging evidence that implicates peroxisomal dysfunction and compromised glymphatic clearance in interfering with lipid balance. Although this field of research has come a long way, the issues of proving causality, standardizing lipidomic techniques, and converting pathway signatures into clinically useful resources persist. Restructuring AD as a lipid network instability disorder offers a systems level model of earlier diagnosis and targeted treatment.},
}

Humans
*Alzheimer Disease/metabolism/genetics/drug therapy
*Lipid Metabolism/physiology
Animals
Lipidomics

@article {pmid42052769,
year = {2026},
author = {Wang, Z and Pan, Y and Shu, M and Zou, L},
title = {The Lysosomal-Associated Protein Transmembrane Family and Neurological Disorders: Therapeutic Potential and Future Research Directions.},
journal = {Journal of integrative neuroscience},
volume = {25},
number = {4},
pages = {47903},
doi = {10.31083/JIN47903},
pmid = {42052769},
issn = {0219-6352},
support = {82201590//National Natural Science Foundation of China/ ; 2022CFB721//Natural Science Foundation of Hubei Province/ ; ZNJC202536//The Translational Medicine, the Interdisciplinary Research Joint Fund of Zhongnan Hospital of Wuhan University/ ; CXPY202535//Science and Technology Innovation Cultivation Fund of Zhongnan Hospital of Wuhan University/ ; },
mesh = {Humans ; *Nervous System Diseases/metabolism/therapy ; Animals ; *Membrane Proteins/metabolism ; Lysosomes/metabolism ; *Oncogene Proteins/metabolism ; },
abstract = {Lysosomal-associated protein transmembrane (LAPTM) family members-including LAPTM4A, LAPTM4B, and LAPTM5-are key regulators of lysosomal integrity, autophagy-lysosome flux, lipid metabolism, and immune responses. Dysregulation of LAPTM proteins contributes to neurological disorders such as Alzheimer's disease, Parkinson's disease, ischemic stroke, and gliomas, affecting neuronal survival, glial homeostasis, neuroinflammation, and tumor progression. In this review, we summarize recent insights into the structural features and molecular mechanisms of LAPTM proteins in the nervous system and highlight their therapeutic potential in promoting protein aggregate clearance, mitigating oxidative stress, regulating microglial polarization, and enhancing tumor immunotherapy. Future research integrating gene therapy, small-molecule modulators, multi-omics profiling, and advanced delivery platforms may enable translation of LAPTM-targeted interventions into clinical practice, offering new avenues for diagnosis, prognosis, and treatment of neurological diseases.},
}

Humans
*Nervous System Diseases/metabolism/therapy
Animals
*Membrane Proteins/metabolism
Lysosomes/metabolism
*Oncogene Proteins/metabolism

@article {pmid42053112,
year = {2026},
author = {Dharshan, SS and Madesh, S and Ramamurthy, K and Radhakrishnan, J and Salamuthu, K and Almutairi, MH and Almutairi, BO and Namasivayam, SKR and Kumaradoss, KM and Arockiaraj, J},
title = {Combating Cadmium-Induced Neurotoxicity, Oxidative Stress, and Inflammatory Pathways Using DOPA-31, a Dioxopiperidinamide Derivative in an In Vivo Zebrafish Model.},
journal = {Journal of biochemical and molecular toxicology},
volume = {40},
number = {5},
pages = {e70872},
doi = {10.1002/jbt.70872},
pmid = {42053112},
issn = {1099-0461},
mesh = {Animals ; Zebrafish ; *Oxidative Stress/drug effects ; *Cadmium/toxicity ; Disease Models, Animal ; *Neuroprotective Agents/pharmacology ; *Inflammation/chemically induced/metabolism/drug therapy ; *Neurotoxicity Syndromes/metabolism/drug therapy/pathology ; Antioxidants/pharmacology ; },
abstract = {Cadmium (Cd), a prevalent environmental toxin and pollutant capable of causing neurodegenerative diseases (NDs) like Alzheimer's and Parkinson's, primarily through oxidative stress, calcium imbalance, and neuroinflammation-induced mechanisms. Cd exposure increases the level of reactive oxygen species (ROS) and disrupts neurotransmitters by lowering antioxidants, leading to neuron death. Cd exposure in zebrafish results in neurodegeneration, with motor, mental, and behavioral impairments. The efficacy of the DOPA-31 intervention at varying concentrations was evaluated through the behavioral tests, biochemical assays for antioxidant enzyme activities (SOD, CAT, GSH, MDA), and histopathological analysis. Additionally, the alterations in expression levels of inflammation (tnf-α, il-1β) and neuroprotective (bdnf, syn2a) genes were also assessed. The Cd exposure exhibited the major deficits in the key behavioral parameters (motor, anxiety, and cognitive impairment). It disrupted antioxidant enzyme activity, increased lipid peroxidation, and elevated acetyl cholinesterase (AChE) activity, leading to cholinergic dysfunction. Histopathology showed extensive neuronal damage and amyloid-like protein aggregation. DOPA-31 at a 20 µM concentration, substantially exhibited antioxidant and AChE activity by reducing oxidative stress and improving motor and cognitive functions. Molecular analysis of DOPA-31 treatment showed significant downregulation of pro-inflammatory markers and upregulation of neuroprotective factors. In addition, DOPA-31 restored behavioral changes by potentially mitigating neuronal damage and protein aggregation caused by the Cd-induced neurotoxicity. This research investigation suggests the novel drug candidate DOPA-31 as a preliminary treatment for Neurodegenerative Disorder (NDD)-like features and warrants further exploration in higher animal models to assess clinical relevance.},
}

Animals
Zebrafish
*Oxidative Stress/drug effects
*Cadmium/toxicity
Disease Models, Animal
*Neuroprotective Agents/pharmacology
*Inflammation/chemically induced/metabolism/drug therapy
*Neurotoxicity Syndromes/metabolism/drug therapy/pathology
Antioxidants/pharmacology

@article {pmid42053135,
year = {2026},
author = {Arslan, B and Gobom, J and Simrén, J and Fahlén, H and Andreasson, U and Andrea Lessa Benedet, and Kvartsberg, H and Zetterberg, H},
title = {Real-world performance of Lumipulse G plasma p-tau217: a six-month experience of a specialized clinical neurochemistry laboratory.},
journal = {Clinical chemistry and laboratory medicine},
volume = {},
number = {},
pages = {},
pmid = {42053135},
issn = {1437-4331},
abstract = {OBJECTIVES: Plasma p-tau217 is a leading blood-based biomarker for Alzheimer's disease (AD), offering high diagnostic accuracy and potential utility for treatment eligibility and monitoring. However, real-world data on concordance between cerebrospinal fluid (CSF) Aβ42/40 and plasma p-tau217 in routine clinical laboratory settings remain limited.

METHODS: We retrospectively evaluated all plasma p-tau217 tests performed in the Clinical Neurochemistry Laboratory at Sahlgrenska University Hospital between August 2025 and March 2026. De-identified plasma p-tau217, additional blood biomarkers, and available CSF results were extracted from the laboratory information system. Concordance between plasma p-tau217 and CSF Aβ42/40 was evaluated by calculating positive and negative percent agreement, with CSF Aβ42/40 used as the reference standard. In addition, diagnostic accuracy for brain amyloid positivity was assessed using two predefined clinical cutoffs for plasma p-tau217 (<0.22 vs. >0.34 ng/L). Internal analytical performance was monitored over a six-month period using commercial quality control materials, with additional evaluation of lot-to-lot consistency for plasma p-tau217.

RESULTS: Among 1,352 plasma p-tau217 measurements, paired CSF Aβ42/40 data were available for 121 individuals. Based on plasma p-tau217 probability categories, 541 samples (40.0 %) were classified as low probability, 228 (16.9 %) as intermediate probability, and 583 (43.1 %) as high probability for amyloid pathology. Using CSF Aβ42/40 as the reference standard, plasma p-tau217 demonstrated a positive percent agreement of 84.5 % (95 % CI: 72.6-92.7 %) and a negative percent agreement of 87.5 % (95 % CI: 73.2-95.8 %). Internal quality control analyses showed good within-batch precision, with coefficients of variation below 7.3 %. Batch-dependent bias was observed in QC measurements, most notably for one batch (+14.4-18.4 %); however, subsequent QC investigations indicated that this deviation originated from the QC material rather than from assay-related performance. Lot-to-lot consistency assessment did not reveal systematic reagent lot-dependent effects during the study period.

CONCLUSIONS: Lumipulse plasma p-tau217 demonstrated stable analytical performance and consistent concordance with CSF Aβ42/40 in routine clinical practice. The observed agreement supports the feasibility of plasma p-tau217 as a supportive tool in the clinical evaluation of AD, while underscoring the need for continued quality control monitoring and prospective evaluation of assay performance.},
}

@article {pmid42053700,
year = {2026},
author = {Lin, C and Qi, L and Gao, X and Hu, L and Qian, B and Deng, Y and Zhou, C and Wang, C and Liu, G and Ding, Q and Lin, Z and Zhu, X and Zhang, M},
title = {Therapeutic Mechanisms of Stem Cell-Derived Exosomes for Neurological Disorders: An Overview.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {},
pmid = {42053700},
issn = {1559-1182},
support = {82271747//the National Natural Science Foundation of China/ ; 82505180//the National Natural Science Foundation of China/ ; ZY2023013//Wenzhou Major Scientific and Technological Innovation Project/ ; 2025C02081//he Zhejiang Provincial Key Research and Development Program/ ; 2025M783998//the China Postdoctoral Science Foundation/ ; },
mesh = {*Exosomes/metabolism/transplantation ; Humans ; Animals ; *Nervous System Diseases/therapy ; *Stem Cells/metabolism ; *Stem Cell Transplantation/methods ; },
abstract = {The current management of neurological disorders remains largely symptomatic. In recent years, stem cell-derived exosomes have emerged as a promising alternative therapeutic strategy. This narrative review synthesizes evidence from preclinical studies investigating the mechanisms and efficacy of exosome-based therapy for neurological conditions. The included studies encompass animal models and in vitro systems. Accumulating preclinical evidence consistently supports the therapeutic potential of stem cell-derived exosomes across several neurological disorders. In Alzheimer's disease models, stem cell-derived exosomes reduce β-amyloid plaque deposition and attenuate neuroinflammation. For Parkinson's disease, they exert neuroprotective effects on dopaminergic neurons. They also inhibit α-synuclein aggregation. In ischemic stroke and spinal cord injury, stem cell-derived exosomes promote functional recovery through multiple mechanisms. These include suppressing ferroptosis, promoting angiogenesis, and stimulating axonal regeneration. Improved delivery strategies, such as intranasal administration and hydrogel encapsulation, have further enhanced brain targeting and treatment durability. Despite these promising preclinical findings, several challenges remain. A primary issue is the lack of standardized preparation protocols. Significant uncertainties also exist regarding long-term safety. Furthermore, pathways for clinical translation are still unclear. Future research should prioritize elucidating the underlying mechanisms of exosome therapy. The refinement of targeted delivery systems is equally important. Finally, advancing rigorously designed clinical trials is crucial to facilitate the translation of these therapies into clinical practice.},
}

*Exosomes/metabolism/transplantation
Humans
Animals
*Nervous System Diseases/therapy
*Stem Cells/metabolism
*Stem Cell Transplantation/methods

@article {pmid42054332,
year = {2026},
author = {Kolmakova, KA and Lobzin, VY and Emelin, AY},
title = {[Sleep disorders in Alzheimer's disease].},
journal = {Zhurnal nevrologii i psikhiatrii imeni S.S. Korsakova},
volume = {126},
number = {4. Vyp. 2},
pages = {56-62},
doi = {10.17116/jnevro202612604256},
pmid = {42054332},
issn = {1997-7298},
mesh = {Humans ; *Alzheimer Disease/complications/physiopathology ; *Sleep Wake Disorders/therapy/etiology/physiopathology ; Memantine/therapeutic use ; Cognitive Behavioral Therapy ; Polysomnography ; },
abstract = {This article investigates the progression of sleep disturbances in Alzheimer's disease (AD) and the mechanisms by which these disturbances may accelerate neurodegeneration. Key electrophysiological patterns identified through polysomnography in patients with AD and sleep disorders are analyzed. Therapeutic interventions are reviewed, with non-pharmacological and pharmacological approaches considered separately. The roles of cognitive behavioural therapy, relaxation techniques, and optimization of sleep conditions are emphasized. Current pharmacological treatment options are discussed, highlighting the need for careful drug selection due to the high risk of adverse effects and the potential dangers of certain medications, such as benzodiazepines and cyclopyrroles, in elderly patients with cognitive impairment. The use of memantine as a foundational therapy is given particular attention, as it may improve both cognitive function and sleep quality.},
}

Humans
*Alzheimer Disease/complications/physiopathology
*Sleep Wake Disorders/therapy/etiology/physiopathology
Memantine/therapeutic use
Cognitive Behavioral Therapy
Polysomnography

@article {pmid42054333,
year = {2026},
author = {Bogolepova, AN and Burd, SG and Lebedeva, AV and Rubleva, YV and Kovalenko, EA and Machnovich, EV and Osinovskaya, NA and Pantina, NV and Kovaleva, II and Bokitko, TA and Alexeeva, GA},
title = {[Myoclonus in Alzheimer's disease].},
journal = {Zhurnal nevrologii i psikhiatrii imeni S.S. Korsakova},
volume = {126},
number = {4. Vyp. 2},
pages = {63-69},
doi = {10.17116/jnevro202612604263},
pmid = {42054333},
issn = {1997-7298},
mesh = {Humans ; *Alzheimer Disease/complications/diagnosis ; *Myoclonus/diagnosis/etiology ; Electroencephalography ; Diagnosis, Differential ; Male ; Aged ; Female ; },
abstract = {Neurodegenerative diseases are often presented with myoclonus, sudden, short-term, involuntary muscle contractions («flinching»). According to the literature, myoclonus in Alzheimer's disease (AD) can occur up to 40-50% in cases of disease with early onset and in atypical forms. Importantly, epileptic myoclonus may indicate a risk of seizures with loss of consciousness, convulsions, and epileptiform activity, which may lead to more rapid progression of cognitive deficits. Diagnosis of myoclonus is essential for timely treatment and improving the quality of life of AD patients. The paper describes the main features of myoclonus in AD, the possibility of using additional examination methods, in particular video-electroencephalographic (video-EEG) monitoring for differential diagnosis and etiology clarification, and also presents a clinical case of a patient with AD and epileptic and non-epileptic myoclonus.},
}

Humans
*Alzheimer Disease/complications/diagnosis
*Myoclonus/diagnosis/etiology
Electroencephalography
Diagnosis, Differential
Male
Aged
Female

@article {pmid42054337,
year = {2026},
author = {Selezneva, ND and Roshchina, IF and Gavrilova, SI},
title = {[Efficacy of choline alfoscerate treatment for subjective cognitive impairment in first-degree relatives of patients with Alzheimer's disease: Results of a comparative 5-year study].},
journal = {Zhurnal nevrologii i psikhiatrii imeni S.S. Korsakova},
volume = {126},
number = {4. Vyp. 2},
pages = {92-99},
doi = {10.17116/jnevro202612604292},
pmid = {42054337},
issn = {1997-7298},
mesh = {Humans ; Male ; Female ; *Alzheimer Disease/drug therapy/genetics ; Middle Aged ; *Glycerylphosphorylcholine/therapeutic use ; *Cognitive Dysfunction/drug therapy ; Aged ; Treatment Outcome ; Neuropsychological Tests ; Prospective Studies ; Follow-Up Studies ; Family ; },
abstract = {OBJECTIVE: To evaluate the five-year change of cognitive functioning in first-degree relatives of patients with Alzheimer's disease (AD) with signs of subjective cognitive impairment (SCI) treated with choline alfoscerate and untreated.

MATERIAL AND METHODS: The study included 122 subjects: 56 (45.9%) in the treatment group and 66 (54.1%) in the control group. Relatives from the treatment group received 4 courses of three-month oral choline alfoscerate therapy (400 mg 3 times a day) every 1.5 years. The study used prospective clinical, psychometric, neuropsychological, and statistical methods. Evaluation included 9 assessment visits using a battery of 10 cognitive scales and tests: in the treatment group, before and after each course of therapy, with a follow-up assessment 3 months after the end of therapy. Assessment visits in the control group were conducted using a similar methodology at the same time points.

RESULTS: On the Clinical Global Impression (CGI-I) scale, varying improvement was observed in the treatment group after each course of therapy and at follow-up examination. By the end of treatment, 96.8% of the subjects reported a marked and moderate improvement. In the control group, after 57 months, deterioration in cognitive functioning was identified at the 39[th], 57[th], and 60[th] months. SCI was converted to mild cognitive impairment syndrome (MCI) in 9.1, 15.2, and 16.7% of cases, respectively. In the treatment group, all psychometric scales and tests showed a significant improvement compared to all baseline mean group indicators after each course of therapy, and at follow-up examination in 4 out of 10 tests. In the control group, significant deterioration in scores on all scales and tests was observed from Month 39 of follow-up.

CONCLUSION: Repeated courses every three months of oral choline alfoscerate therapy for five years led in the vast majority of observations to improved cognitive functioning in persons from the treatment group at increased risk for developing AD, while untreated relatives had decreasing cognitive functioning, including a 16.7% rate of transformation of SCI into MCI.},
}

Humans
Male
Female
*Alzheimer Disease/drug therapy/genetics
Middle Aged
*Glycerylphosphorylcholine/therapeutic use
*Cognitive Dysfunction/drug therapy
Aged
Treatment Outcome
Neuropsychological Tests
Prospective Studies
Follow-Up Studies
Family

@article {pmid42054665,
year = {2026},
author = {Liu, J and Wang, X and Shieu, B and Garcia, DD and Vondenberger, A and Xu, J and Zhang, Y and Monjur, M and Wang, W and Nirjon, S and Svatek, R and Gonzales, M and Patel, N and Song, L},
title = {An Internet of Things-Based Audio and Radio Connected System Supporting Older Adults With Physical and Cognitive Health Challenges: Qualitative Stakeholder-Informed Design Study.},
journal = {JMIR formative research},
volume = {10},
number = {},
pages = {e76341},
doi = {10.2196/76341},
pmid = {42054665},
issn = {2561-326X},
mesh = {Humans ; Qualitative Research ; Aged ; Male ; Female ; *Internet of Things ; Caregivers/psychology ; Aged, 80 and over ; Stakeholder Participation ; Chronic Disease/therapy/psychology ; Middle Aged ; Alzheimer Disease ; },
abstract = {BACKGROUND: Older adults managing chronic illnesses, such as cancer and Alzheimer disease and related dementias (ADRD), often experience significant physical or cognitive impairments that hinder daily activities and increase caregiver burden. Smart Internet of Things (IoT) technologies offer promising solutions by enabling passive monitoring, timely reminders, and personalized support at home. However, these technologies must be carefully tailored to accommodate users' individualized needs and preferences.

OBJECTIVE: This formative qualitative study aimed to explore stakeholder perspectives, including patients, caregivers, health care providers, and technical experts, on the use of smart home-based IoT systems to support chronic illness management. The goal was to inform the early development of the audio and radio connected (AURA) system, an IoT prototype integrating Wi-Fi sensing, wearable trackers, and voice-assistive features.

METHODS: Semistructured interviews were conducted with 6 patients who underwent postostomy creation for colorectal or bladder cancer treatment and 5 patients with ADRD and their caregivers. Input from additional stakeholders, including 2 health care providers, 2 community health workers, and 2 computer scientists, was also included in the report. Stakeholders reviewed a demonstration video depicting the conceptual features of the AURA system. Interviews explored stakeholders' needs and preferences for using such systems. Thematic analysis was guided by the extended Unified Theory of Acceptance and Use of Technology 2 (UTAUT2) framework, with 5 adapted constructs: performance expectancy, effort expectancy, social influence, facilitating conditions, and hedonic motivation and habit.

RESULTS: Stakeholders identified distinct yet complementary needs across populations. Patients with cancer emphasized physical health monitoring, integration with health care systems, and customization; ADRD stakeholders prioritized routine support, emotional engagement, and simplicity; caregivers and clinicians emerged as key influencers of adoption. Barriers included privacy concerns, technology literacy, and fatigue, while facilitators included perceived caregiving support, streamlined interfaces, and electronic health record integration. Patients with cancer focused on motivational cues for physical activity, while emotional engagement and habit were more prominent for ADRD users.

CONCLUSIONS: Stakeholder insights underscore the importance of designing adaptable, user-centered IoT systems that reflect the varied capabilities and care needs of older adults with chronic illnesses. These findings informed the design of the AURA prototype and highlighted theoretical considerations for technology acceptance in health care. Future work will test AURA in real-world settings to evaluate usability, acceptability, and clinical relevance.},
}

Humans
Qualitative Research
Aged
Male
Female
*Internet of Things
Caregivers/psychology
Aged, 80 and over
Stakeholder Participation
Chronic Disease/therapy/psychology
Middle Aged
Alzheimer Disease

@article {pmid42054867,
year = {2026},
author = {Coles, M and Rosa Porto, R and Chesworth, R and Steiner-Lim, GZ and Karl, T},
title = {Combining cannabidiol and delta-9-tetrahydrocannabinol at a 50:3 ratio - a new therapeutic strategy for APPSwe/PS1ΔE9 transgenic mice?.},
journal = {Neurobiology of aging},
volume = {164},
number = {},
pages = {79-90},
doi = {10.1016/j.neurobiolaging.2026.04.003},
pmid = {42054867},
issn = {1558-1497},
abstract = {Preclinical evidence suggests that cannabidiol (CBD) can ameliorate Alzheimer's disease (AD)-related pathologies, including amyloid-β aggregation and tau hyperphosphorylation, and can reverse and prevent cognitive decline in AD rodent models. Interestingly, low-dose delta-9-tetrahydrocannabinol (THC) can improve cognition in aged mice, and 1:1 CBD+THC appears to exhibit a greater therapeutic profile in AD mouse models than either phytocannabinoid alone. Here, the potential of chronic treatment with 50 mg/kg bodyweight CBD combined with 3 mg/kg THC to reverse the behavioural deficits of adult APPSwe/PS1ΔE9 (APP/PS1) AD transgenic mice was evaluated. 14-month-old male and female transgenic mice and their wild type-like littermates were used. They were treated via daily intraperitoneal injection with CBD+THC treatment (or vehicle) for 3 weeks prior to and throughout behavioural assessment. CBD+THC significantly improved the initial localisation of the reward zone during a spatial memory probe trial in APP/PS1 mice and restored the increased acoustic startle response of APP/PS1 females. APP/PS1 mice had deficient object recognition memory and impaired spatial learning, neither of which were restored following combined cannabinoid treatment. Interestingly, CBD+THC impaired social recognition of APP/PS1 males. Treatment reduced sensorimotor gating in females. In males, treatment decreased risk assessment behaviour, and reduced acoustic startle. CBD+THC treatment had mild therapeutic properties but also off-target effects, suggesting that CBD+THC might be less preferable than CBD alone in a mouse model of advanced AD. Further research into alternate cannabinoid dosage and dose ratios is required to elucidate the potential of cannabinoid combination therapies for AD more comprehensively.},
}

@article {pmid42055092,
year = {2026},
author = {Høilund-Carlsen, PF and Alavi, A and Andalib, S and Castellani, RJ and Costa, T and de Girolamo, G and Espay, AJ and Neve, RL and Perry, G and Revheim, ME and Robakis, NK and Sensi, SL and Vissel, B and Barrio, JR},
title = {Serious Side Effects of Alzheimer's Immunotherapy Demand Scrutiny.},
journal = {Ageing research reviews},
volume = {},
number = {},
pages = {103151},
doi = {10.1016/j.arr.2026.103151},
pmid = {42055092},
issn = {1872-9649},
abstract = {Monoclonal antibodies targeting amyloid-β, i.e., lecanemab and donanemab, have recently been approved for treating early Alzheimer's disease (AD). Though these antibodies are by many considered milestones in AD therapy, clinical approvals have been inconsistent due to ongoing debates over their clinical benefit and safety. The reported cognitive decline slowing is modest and often below the thresholds for clinically significant differences on outcome scales. Moreover, these therapies are linked to adverse effects, including infusion reactions, headaches, and nausea, as well as more serious issues like amyloid-related imaging abnormalities (ARIAs), the long-term impact of which remains unclear. In this Viewpoint article, we highlight three safety concerns: ARIAs, accelerated brain volume loss, and therapy-related deaths. ARIAs occur much more frequently in treated AD patients than in placebo groups, yet their functional consequences remain poorly understood. Evidence also suggests that treatment with anti-amyloid antibodies may lead to more brain tissue loss than placebo treatments, though this has received limited attention in trials and regulatory evaluations. Finally, reliable data on therapy-related mortality is scarce due to insufficient access to detailed clinical and neuropathological information. These issues underscore significant uncertainties in assessing the risk-benefit profile of anti-amyloid therapies. A more systematic investigation-including routine brain volume monitoring, functional PET imaging, and independent death evaluations-is crucial for a comprehensive understanding of both benefits and risks in regulatory and clinical decisions.},
}

@article {pmid42055093,
year = {2026},
author = {Nakum, B and Vejpara, D and Faldu, K and Soni, R and Shah, J},
title = {Tiny Titans, Big Promise: Nanotechnology and microRNA in the Fight Against Alzheimer's Disease.},
journal = {Ageing research reviews},
volume = {},
number = {},
pages = {103149},
doi = {10.1016/j.arr.2026.103149},
pmid = {42055093},
issn = {1872-9649},
abstract = {Alzheimer's disease (AD) remains the most common neurodegenerative disorder. It is driven by complex molecular dysfunctions that includes amyloid aggregation, tau pathology, and neuroinflammation. It leads to cognitive deficits and memory loss in elderly people. Current treatments offer limited symptomatic relief. Hence, there is urgent need for innovative therapeutics and diagnostic approaches. Among emerging therapeutic targets, microRNAs (miRNAs) have pivotal role in regulating genes linked to amyloid precursor protein (APP), tau phosphorylation, and inflammatory cascades. This review explores the synergistic as well as individual potentials of nanotechnology and microRNAs (miRNAs) in AD. Nanotechnology aids in targeted drug delivery, enhanced imaging and theranostic capabilities; whereas miRNAs are key regulators of gene expression. Beyond pathogenesis, circulating and cerebrospinal miRNAs serve as minimally invasive biomarkers capable of distinguishing AD from mild cognitive impairment, offering early diagnostic potential. However, therapeutic translation faces challenges of instability, poor bioavailability, and limited blood-brain barrier (BBB) permeability. Here, combination of nanotechnology with miRNA is a compelling solution. Engineered nano-based system enhance miRNA stability, protect them from enzymatic degradation, and enable targeted delivery. This review highlights the synergistic use of nanotechnology and miRNA for AD diagnostics and therapeutics as a multifaceted strategy. Together, these advances promise a path toward early diagnosis and personalized treatment options for AD.},
}

@article {pmid42055109,
year = {2026},
author = {Zhu, Y and Zhang, H and Zhang, Z and Song, G and Fu, J and Wang, H},
title = {The role of ultrasound in addressing neurodegenerative diseases: A review of mechanisms, applications, and challenges.},
journal = {Neuroscience},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.neuroscience.2026.04.024},
pmid = {42055109},
issn = {1873-7544},
abstract = {With the aging of the global population, neurodegenerative diseases have become a major public health challenge. Currently, there are many limitations in the traditional treatment of neurodegenerative diseases, such as medicine, deep brain stimulation, transcranial magnetic stimulation, and transcranial direct current stimulation, including the inability to penetrate the blood-brain barrier (BBB) accurately and challenges in achieving precise and quantitative control during the treatment process. Ultrasound is an emerging neural modulation technology that stands out for its non-invasive nature, precise targeting, and unique ability to penetrate the BBB, demonstrating tremendous application potential. In this review, we summarized the common types of neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), and Amyotrophic lateral sclerosis (ALS), and the limitations of traditional treatments. It delves into the physical principles, classification, mechanisms, and unique advantages of ultrasound therapy in neuromodulation. It provides a detailed account of the current status of application of ultrasound in neurodegenerative diseases, and represents the advantages and challenges currently faced by ultrasound therapy, which offers insights into future research directions and technological improvements.},
}

@article {pmid42055146,
year = {2026},
author = {Lin, C and Xu, Z and Yan, J and Liu, B and Li, F},
title = {Icariin Promotes Lysosomal Degradation of Amyloid-β Precursor Protein via Enhanced Endosome-Lysosome Trafficking to Reduce Amyloid-β Accumulation and Improve Cognitive Function in Alzheimer's Disease Models.},
journal = {Brain research bulletin},
volume = {},
number = {},
pages = {111906},
doi = {10.1016/j.brainresbull.2026.111906},
pmid = {42055146},
issn = {1873-2747},
abstract = {Alzheimer's disease (AD) represents a devastating global public health crisis, characterized by progressive cognitive decline and memory impairment, with its prevalence and associated disability rates rising exponentially amid global population aging. The pathological hallmarks of AD include the accumulation of amyloid-beta (Aβ) plaques and hyperphosphorylated tau protein tangles, which primarily arise from the aberrant processing of amyloid-β precursor protein (AβPP). Currently, approved therapeutic strategies for AD only provide symptomatic relief, and there is a critical unmet need for effective disease-modifying treatments-particularly those targeting the transport and degradation mechanisms of AβPP, which remain poorly understood and under-explored. This study aims to elucidate the effects of icariin on AβPP subcellular localization and degradation via the lysosomal pathway in both APP/PS1 transgenic mouse model and human-APP695-overexpressing cell line. Combining behavioral assessments with biochemical analyses and confocal microscopy, this study demonstrates that prolonged icariin treatment significantly enhances cognitive function, reduces levels of AβPP, BACE1, and Aβ, and promotes the lysosomal degradation of AβPP by facilitating its transport from early endosomes to lysosomes. The findings reveal that icariin effectively mitigates Aβ generation and cognitive deficits by shortening the residence time of AβPP in early endosomes, thereby filling a key knowledge gap in AβPP metabolism and uncovering a novel regulatory mechanism. These results not only establish icariin as a promising candidate for AD intervention but also propose a new therapeutic avenue targeting AβPP degradation mechanisms, with substantial implications for both basic research and clinical applications in AD treatment. Future investigations should focus on evaluating the translational potential of icariin and characterizing its pharmacological profile to optimize clinical efficacy and safety, addressing the urgent need for disease-modifying therapies for this devastating neurodegenerative disorder.},
}

@article {pmid42044556,
year = {2026},
author = {Braak, S and Mennes, M and Su, T and Pijnenburg, Y and Bakker, G and Arango, C and van der Wee, N and Bauduin, S and Ortiz-Tallo Moya, A and Lopez-Morinigo, JD and Dawson, GR and Abrahams, AB and Beckenstrom, AC and Beckmann, CF and Marston, HM and Penninx, BWJH and Kas, MJH},
title = {Social dysfunction and default mode network functional integrity in neuropsychiatric disorders: A cross-disorder replication and generalization study.},
journal = {European neuropsychopharmacology : the journal of the European College of Neuropsychopharmacology},
volume = {110},
number = {},
pages = {112847},
doi = {10.1016/j.euroneuro.2026.112847},
pmid = {42044556},
issn = {1873-7862},
abstract = {Cross-disorder research and replication of neuroimaging findings remains scarce. Social dysfunction is an early manifestation across diverse neuropsychiatric disorders that may relate to altered default mode network (DMN) integrity. This study aimed to replicate previous findings linking social dysfunction with diminished resting-state DMN functional connectivity and altered task-based DMN functional activation in response to emotional faces across schizophrenia (SZ), Alzheimer's disease (AD), and healthy controls (HC), and to extend these findings to major depressive disorder (MDD). Resting-state fMRI and task-based fMRI data on implicit facial emotional processing were acquired in an overlapping cohort (resting-state fMRI: N=167; SZ=32, MDD=44, AD=29, HC=62. Task-based fMRI: N=152; SZ=30, MDD=42, AD=26, HC=54). Additionally, mega-analyses (N=317 for resting-state fMRI; N=291 for task-based fMRI) of the current and a prior independent sample were conducted. Social dysfunction was indexed with the Social Functioning Scale (SFS) and the De Jong-Gierveld Loneliness (LON) scale. The association between higher mean SFS+LON social dysfunction scores and diminished DMN connectivity within the dorsomedial prefrontal cortex across SZ/AD/HC participants was replicated, and extended to MDD patients. Similar observations within the dorsomedial and rostromedial prefrontal cortex were found in the mega-analysis. Associations between social dysfunction and DMN activation in response to sad and happy faces were not replicated or found in the mega-analysis. To conclude, diminished dorsomedial prefrontal cortex DMN connectivity emerged as a transdiagnostic neurobiological marker for social dysfunction, suggesting a potential treatment target for precision medicine approaches. DMN functional responses to emotional faces may not be a sensitive biomarker for social dysfunction.},
}

@article {pmid42045164,
year = {2026},
author = {Pozzi-Ruiz, V and Giner de Gracia, A and Glauser, L and Romani, M and Gunter-Rahman, F and González-Ramón, A and Haj-Yahya, M and Kolla, R and Burns, AM and Lashuel, HA and Auwerx, J and Gräff, J and Sanchez-Mut, JV},
title = {The PM20D1-OLE pathway induces microglia rewiring to ameliorate Alzheimer disease.},
journal = {Cell death & disease},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41419-026-08791-1},
pmid = {42045164},
issn = {2041-4889},
support = {PID2022-143263OB-I00//Ministry of Economy and Competitiveness | Agencia Estatal de Investigación (Spanish Agencia Estatal de Investigación)/ ; PRE2020-093825//Ministry of Economy and Competitiveness | Agencia Estatal de Investigación (Spanish Agencia Estatal de Investigación)/ ; PRE2020-093389//Ministry of Economy and Competitiveness | Agencia Estatal de Investigación (Spanish Agencia Estatal de Investigación)/ ; ERC-AdG-787702//EC | EU Framework Programme for Research and Innovation H2020 | H2020 Priority Excellent Science | H2020 European Research Council (H2020 Excellent Science - European Research Council)/ ; SNSF 31003A_179435//Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung (Swiss National Science Foundation)/ ; },
abstract = {There is increasing evidence of microglia participation in Alzheimer's disease (AD), which incentives their modulation to intercept the disease. Here, we describe a new mechanism by which the recently AD-associated Peptidase M20 Domain Containing 1 (PM20D1) instructs microglia to tackle AD. We show that the PM20D1-derived N-oleoyl-Leucine (OLE) improves AD pathologies in two animal models of AD. OLE induces microglia association with amyloid beta (Aβ) plaques, reduce their size, number and toxicity, and leads to enhanced neuroprotection and cognition. Furthermore, OLE also increases Aβ chemotaxis and clearance in microglia cultures and enhances cell viability in neurons subjected to AD-related stressors. Finally, we also find evidence for a PM20D1- and OLE-mediated microglia association with amyloid plaques and neuroprotection in human AD brains. In sum, our results provide further insight into the protective role of PM20D1 in AD and support the use of OLE as a microglia-modifying treatment for AD.},
}

@article {pmid42047299,
year = {2026},
author = {Phares, S and Kremer, I and Wall, JK and Wood, J and Baumgart, M and Dickson, S and Fickie, M and Hubbard, T and Jannati, A and Monane, M and Rivet, C and Hirsch, G},
title = {System changes to empower primary care in Alzheimer's disease detection and care.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {4},
pages = {e71276},
doi = {10.1002/alz.71276},
pmid = {42047299},
issn = {1552-5279},
mesh = {Humans ; *Alzheimer Disease/diagnosis/therapy ; *Primary Health Care ; United States ; Delivery of Health Care ; },
abstract = {Despite advances in disease-modifying treatments, significant barriers in the evaluation and clinical management of people with early Alzheimer's disease (AD) remain. These barriers have been documented in scientific literature and increasingly call for primary care to play a larger role in the detection, diagnosis, treatment, and monitoring of AD. Drawing upon the work of a multistakeholder consortium, this article identifies systemic and structural barriers that hinder primary care professionals in the United States from playing a larger role. We propose solutions to these barriers and call for evolution of the U.S. healthcare system to ensure it is prepared to adapt to the rapidly progressing scientific and societal landscape and meet the growing needs of people affected by the early stages of AD.},
}

Humans
*Alzheimer Disease/diagnosis/therapy
*Primary Health Care
United States
Delivery of Health Care

@article {pmid42033998,
year = {2026},
author = {Yang, B and Earnest, T and Bilgel, M and Albert, MS and Johnson, SC and Davatzikos, C and Erus, G and Masters, CL and Resnick, SM and Miller, MI and Bakker, A and Morris, JC and Benzinger, TLS and Gordon, BA and Sotiras, A and , and , },
title = {Predicting future cognitive impairment in preclinical Alzheimer's disease using amyloid PET and MRI: A multisite machine learning study.},
journal = {Neurobiology of aging},
volume = {165},
number = {},
pages = {8-23},
doi = {10.1016/j.neurobiolaging.2026.04.005},
pmid = {42033998},
issn = {1558-1497},
abstract = {Predicting the likelihood of developing Alzheimer's disease (AD) dementia in at-risk individuals is important for the design of and optimal recruitment for clinical trials of disease-modifying therapies. Machine learning (ML) has been shown to excel in this task; however, there remains a lack of models developed specifically for the preclinical AD population, who display early signs of abnormal brain amyloidosis but remain cognitively unimpaired. Here, we trained and evaluated ML classifiers to predict whether individuals with preclinical AD will progress to mild cognitive impairment or dementia within multiple fixed time windows, ranging from one to five years. Models were trained on regional imaging features extracted from amyloid positron emission tomography and magnetic resonance imaging pooled across seven independent sites and from two amyloid radiotracers ([[18]F]-florbetapir and [[11]C]-Pittsburgh-compound-B). Out-of-sample generalizability was evaluated via a leave-one-site-out and leave-one-tracer-out cross-validation. Classifiers achieved an out-of-sample receiver operating characteristic area-under-the-curve of 0.66 or greater when applied to all except one hold-out sites and 0.72 or greater when applied to each hold-out radiotracer. Additionally, when applying our models in a retroactive cohort enrichment analysis on A4 clinical trial data, we observed increased statistical power of detecting differences in amyloid accumulation between placebo and treatment arms after enrichment by ML stratifications. As emerging investigations of new disease-modifying therapies for AD increasingly focus on asymptomatic, preclinical populations, our findings underscore the potential applicability of ML-based patient stratification for recruiting more homogeneous cohorts and improving statistical power for detecting treatment effects for future clinical trials.},
}

@article {pmid42034805,
year = {2026},
author = {Monteiro, R and Dunn, JT and Rodriguez, G and Fisher, DW and Dong, H},
title = {Targeting central immune signaling enhances the effects of methylphenidate in alleviating apathy-like behavior in 5xFAD mice.},
journal = {Scientific reports},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41598-026-49172-0},
pmid = {42034805},
issn = {2045-2322},
support = {R01AG062249-05, 5R01AG079989-03//National Institute of Aging/ ; },
abstract = {Beyond cognitive impairment, Alzheimer's disease (AD) is frequently accompanied by apathy, the most prevalent and burdensome neuropsychiatric symptom (NPS). Apathy significantly impacts AD onset and progression, yet its molecular underpinnings remain unclear. Our previous RNA-sequencing analysis revealed abnormal immune gene expression uniquely associated with apathy in AD patients. In this study, we investigated whether changes in these immune related genes are also linked to apathy-like behavior, and whether administration of C3a receptor antagonist SB290157, alone or with methylphenidate, modifies apathy-like behaviors in 5xFAD mice. We first validated the apathy-related immune hub genes identified in human AD in the prefrontal cortex (PFC) of 16-18 month-old 5xFAD mice using RT-qPCR. Then separate cohorts of similarly aged 5xFAD mice received SB290157 and/or methylphenidate for three weeks. Our results showed that elevated immune hub genes Tyrobp, C3, C3ar, C1qa, C1qb, and C1qc were strongly correlated with apathy-like behavior in 5xFAD mice. Combined SB290157 and methylphenidate treatment improved nest-building behavior, reduced C3 and C3ar expression as well as restored dendritic spine density in the PFC. Our results confirm complement-mediated immune dysregulation is linked to apathy and suggest that co-targeting complement and catecholaminergic pathways may offer a novel therapeutic strategy for alleviating apathy in AD.},
}

@article {pmid42036797,
year = {2026},
author = {Bonta, KM and Li, JS and Tun, SM and Fredericks, CA},
title = {Sleep duration and amyloid status moderate the association between mood symptoms and amygdalar tau in preclinical Alzheimer's disease.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {4},
pages = {e71447},
doi = {10.1002/alz.71447},
pmid = {42036797},
issn = {1552-5279},
support = {K23AG059919/NH/NIH HHS/United States ; 2019-AACSF-644153/ALZ/Alzheimer's Association/United States ; //The McCance Foundation/ ; },
mesh = {Humans ; *Alzheimer Disease/metabolism/diagnostic imaging/psychology ; Male ; Female ; *tau Proteins/metabolism ; Positron-Emission Tomography ; Aged ; *Amygdala/metabolism/diagnostic imaging ; *Anxiety/metabolism ; *Sleep/physiology ; *Depression/metabolism ; Longitudinal Studies ; *Amyloid beta-Peptides/metabolism ; Aged, 80 and over ; Prodromal Symptoms ; Sleep Duration ; },
abstract = {INTRODUCTION: Anxiety and depressive symptoms are common in Alzheimer's disease (AD), yet their relationships with amyloid, tau, and sleep remain unclear. We examined whether amyloid status and sleep duration moderate the relationships between anxiety and depressive symptoms and amygdalar tau burden in cognitively unimpaired older adults at risk for AD.

METHODS: Participants (n = 393) from the Anti-Amyloid Treatment in Asymptomatic Alzheimer's Disease (A4) and the Longitudinal Evaluation of Amyloid Risk and Neurodegeneration (LEARN) studies underwent tau and amyloid positron emission tomography imaging. Anxiety and depressive symptoms were evaluated using the State-Trait Anxiety Inventory and Geriatric Depression Scale. Sleep duration was self-reported.

RESULTS: Positive amyloid status moderated the relationship between depressive symptoms and amygdalar tau. Sleep duration moderated the relationship between anxiety and amygdalar tau, such that greater anxiety symptoms were associated with higher tau levels at shorter sleep durations.

DISCUSSION: Findings suggest biological and behavioral factors jointly influence neuropsychiatric symptom-tau relationships in preclinical AD, supporting an interactive model of early disease vulnerability.},
}

Humans
*Alzheimer Disease/metabolism/diagnostic imaging/psychology
Male
Female
*tau Proteins/metabolism
Positron-Emission Tomography
Aged
*Amygdala/metabolism/diagnostic imaging
*Anxiety/metabolism
*Sleep/physiology
*Depression/metabolism
Longitudinal Studies
*Amyloid beta-Peptides/metabolism
Aged, 80 and over
Prodromal Symptoms
Sleep Duration

@article {pmid42037680,
year = {2026},
author = {Sirajo, MU and Obie, R and Mukhtar, AI and Abdullahi, NM and Taniyohwo, EM and Oyem, JC and Badamasi, IM},
title = {Targeting VDR-RXR heterodimerization in neurodegenerative diseases: a hypothetical framework for combined vitamin D3 and vitamin A therapy.},
journal = {Frontiers in neurology},
volume = {17},
number = {},
pages = {1754364},
pmid = {42037680},
issn = {1664-2295},
abstract = {Neurodegenerative diseases such as Alzheimer's and Parkinson's disease are characterized by progressive neuronal loss, oxidative stress, and limited treatment options. While vitamin D3 has demonstrated neuroprotective potential, we hypothesize that its co-administration with vitamin A may enhance therapeutic effects via synergistic interactions between their nuclear receptors (the vitamin D Receptor (VDR) and Retinoid X Receptor (RXR)). The interaction leads to the formation of a heterodimer, which regulates genes involved in neuronal survival, inflammation, and oxidative balance. A comprehensive literature review was conducted to evaluate the mechanisms underlying Vitamin D3's neuroprotection and Vitamin A's modulatory role through RXR activation, focusing on studies exploring the VDR-RXR heterodimer in Alzheimer's and Parkinson's disease models. Evidence indicates that vitamin D3 mitigates neurodegeneration by upregulating neuroprotective genes, reducing oxidative stress, and modulating calcium homeostasis, with these effects amplified by RXR activation. The VDR-RXR heterodimer interaction appears critical for enhancing transcriptional activity, promoting neuronal resilience, while potentially slowing neurodegeneration progression. We propose that combined vitamin D3 and vitamin A supplementation could offer a promising therapeutic strategy by synergistically optimizing VDR-RXR signaling, thereby improving neuroprotection. This hypothesis requires validation through an integrated approach that includes molecular, cellular, behavioral, and translational neuroimaging methods to investigate neuroprotective effects associated with VDR-RXR co-activation.},
}

@article {pmid42038088,
year = {2026},
author = {Permoda-Pachuta, A and Obszanski, P and Grad, Z and Futyma-Jędrzejewska, M and Ziemecki, P and Dominiak, M},
title = {Depression as an early symptom and risk factor of dementia - a narrative review.},
journal = {Frontiers in psychiatry},
volume = {17},
number = {},
pages = {1786179},
pmid = {42038088},
issn = {1664-0640},
abstract = {Depression is a common psychiatric disorder, while dementia represents a growing global health challenge, particularly in aging populations. Although substantial progress has been made in pharmacotherapy, neurodegenerative processes can only be partially slowed, and disease progression cannot be completely halted. Neurodegenerative diseases therefore remain largely incurable, underscoring the importance of early recognition and intervention. This raises an important clinical and conceptual question: does depression represent an early manifestation of dementia, act as a risk factor for its development or both? Understanding these relationships is essential for accurate diagnosis, appropriate treatment, and timely implementation of preventive strategies. This article presents a narrative review of the literature examining the complex relationship between depression and dementia, with a focus on clinical presentation, diagnostic challenges, and neurobiological mechanisms. Neuroimaging techniques such as MRI and PET, and in selected contexts SPECT, support the differential diagnosis of depression and dementia, although limitations in sensitivity and specificity persist. Inflammation has been extensively investigated as a shared pathological mechanism underlying both conditions. Emerging evidence also suggests that anti-amyloid therapies may be associated with improvements in depressive symptoms in selected patient populations, further highlighting overlapping pathophysiological pathways between depression and dementia. Improved understanding of the interplay between depression and dementia may facilitate earlier diagnosis, reduce diagnostic uncertainty, and support the development of more effective preventive and therapeutic strategies.},
}

@article {pmid42038337,
year = {2026},
author = {Hong, R and Han, J and Dong, F and Kalsoom, UE and Cao, C and Zhou, A and Wu, Q and Qu, X},
title = {Cynanchum bungei Decne-derived extracellular vesicles alleviate cognitive impairment and pathological damage in Alzheimer's disease.},
journal = {Frontiers in cellular neuroscience},
volume = {20},
number = {},
pages = {1798965},
pmid = {42038337},
issn = {1662-5102},
abstract = {INTRODUCTION: Cynanchum bungei Decne (CB) is known for its therapeutic benefits for neurodegenerative conditions as anti-inflammatory, antioxidant, and barrier significantly limits their potential advantages. Given the ability of crossing the barrier with minimal toxicity, extracellular vesicles derived from CB (CB-EVs) were utilized as an innovative approach to mitigate Alzheimer's disease (AD).

METHODS: CB-EVs were isolated using gradient ultracentrifugation and identified via TEM imaging, nanoparticle tracking analysis, marker identification, and in vivo imaging system. Ten-month-old triple transgenic AD (3xTg-AD) mice received intravenous administration of CB-EVs at doses of 10 or 20 mg/kg every 3 days for the cognitive and pathological assessments. The human APP Swedish mutation transgenic SH-SY5Y cells were constructed as Aβ-induced neural damage model, and different concentrations of CB-EVs were added into medium to analyze its roles on cell viability, transcriptome changes, oxidative stress, and mitochondrial damage.

RESULTS: CB-EVs exhibited standard morphological and molecular traits, accumulating in the cerebral cortex and hippocampus. Two months of CB-EVs treatment alleviated cognitive impairments, diminished Aβ plaque, reduced Tau protein hyperphosphorylation, and lessened neuronal loss in 3xTg-AD mice. In transgenic SH-SY5Y cells, CB-EVs improved cell viability, enhanced superoxide dismutase activity, downregulated oxidative stress related NUPR1 and CHOP expression, decreased reactive oxygen species, lipid peroxidation, and malondialdehyde levels, reduced mitochondrial damage.

CONCLUSION: These results demonstrated that CB-EVs could protect neurons from oxidative stress, attenuate cognitive impairment and pathological damage in AD.},
}

@article {pmid42038539,
year = {2026},
author = {K, V and Jaisankar, N},
title = {Design of a deep learning prediction model for Alzheimer's and Parkinson's Disease using MRI images.},
journal = {Frontiers in artificial intelligence},
volume = {9},
number = {},
pages = {1777236},
pmid = {42038539},
issn = {2624-8212},
abstract = {INTRODUCTION: Alzheimer's disease (AD) and Parkinson's disease (PD) are types of neurodegenerative diseases that affect the body and get worse over time. The cause of AD mainly involves the buildup of protein which are abnormal, issues with the immune reaction, death of neurons. Different from this, the death of the neurons that make dopamine leads to PD and causes both motor and non-motor problems. MRI images are used to provide an early and correct diagnosis to enable timely treatment planning and management of the disease.

METHODS: In this paper, a design of an AI-based deep learning framework is proposed for the classification of neurodegenerative disease based on the brain MRI data. The pipeline that we propose begins with data preparation including data augmentation using InceptionGAN for augmentation of the dataset and fixing of class imbalance issues. A composite method of feature extraction using ConvNeXt and MaxViT along with the Cross-Fusion Attention model, worked well to capture local and global spatial features. Bayesian Optimization and Genetic Algorithm are used to optimize hyperparameters for improving the performance of the model.

RESULTS: The Hybrid Deep Neural Network (HDNN) is the last classifier with an accuracy of 97.4%. Based on performance accuracy, F1-score, the model is strong and reliable. We used Gradient-weighted Class Activation Mapping++ to explain how regions of interest in the brain influence our model's decisions.

DISCUSSION: This study offers an interpretable and high-performing deep learning framework for the early and precise prediction of neurodegenerative disorders utilizing MRI imaging, thereby enhancing clinical decision-making and patient care.},
}

@article {pmid42038695,
year = {2026},
author = {Wang, X and Tian, L},
title = {The therapeutic efficacy of transcranial direct current stimulation in managing Alzheimer's disease: a systematic review and meta-analysis.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1726469},
pmid = {42038695},
issn = {1663-4365},
abstract = {OBJECTIVE: The present study aimed to investigate the therapeutic efficacy of transcranial direct current stimulation (tDCS) for Alzheimer's disease (AD) and identify potential influential factors.

METHODS: A comprehensive literature search was conducted in PubMed, Embase, Web of Science, and the Cochrane Library up to April 2025. Eligible studies were randomized controlled trials (RCTs) in which tDCS was the sole differential intervention between study arms. The pooled effects of tDCS on patients' global cognition, language, memory, executive function, and emotion were evaluated. Subgroup analyses were also performed to identify potential influential factors.

RESULTS: A total of 23 studies involving 24 trials and 823 mild to moderate AD patients were included. Our meta-analysis showed that tDCS significantly improved global cognition in AD patients (standardized mean difference [SMD] = 0.66; 95% confidence interval [CI], 0.38-0.95; p < 0.01), but had no significant effects on language or emotion. Subgroup analyses further revealed that significant memory improvement was observed in patients who received ≤ 10 sessions of tDCS and those with >6 years of education. Additionally, executive function was improved in patients who received stimulation on the left dorsolateral prefrontal cortex and in tDCS groups with ≤ 10 sessions. Moreover, improved executive function was observed in patients with 6-10 years of education, but not in other subgroups.

CONCLUSION: tDCS treatment leads to improvements in global cognition, memory, and executive function in AD patients, but not in language or psychomotor symptoms. However, due to the relatively high heterogeneity of the included data, further well-designed studies are warranted before tDCS can be established as a standard therapeutic approach for AD.},
}

@article {pmid42038702,
year = {2026},
author = {Zhao, S and Shi, H and Guan, C and Zeng, Q and Zhang, C and Wan, Y},
title = {Research on Alzheimer's disease MRI image classification based on spatial attention mechanism.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1657578},
pmid = {42038702},
issn = {1663-4365},
abstract = {INTRODUCTION: Early diagnosis of Alzheimer's Disease (AD) is crucial for improving patient quality of life and treatment outcomes. However, accurately classifying MRI scans of AD remains challenging due to the subtle and spatially complex nature of lesion regions. This study proposes a novel bidirectional spatial attention mechanism to enhance the focus on key pathological features in AD MRI images, aiming to improve classification accuracy and support earlier intervention.

METHODS: To enhance model performance, we introduced a customized bidirectional spatial attention module (ATT) integrated into a Swin-Tiny Transformer backbone. Unlike conventional attention methods, the ATT module generates spatial attention maps by adaptively pooling features along both vertical and horizontal orientations, allowing refined adjustment of attention weights across different image regions. Furthermore, to address issues of limited sample size and class imbalance, we employed data augmentation and expansion strategies, enriching the diversity of training data. The model was trained and evaluated on the augmented OASIS1 dataset.

RESULTS: The improved Swin-Tiny+ATT model demonstrated significant performance gains across all key metrics on the augmented dataset. Compared to the baseline Swin Transformer, accuracy improved from 84.83% to 87.96%, recall from 89.82% to 91.92%, precision from 85.27% to 91.98%, and the F1 score from 87.26% to 91.89%. These results confirm that the ATT module effectively enhances the model's ability to capture complex spatial features and identify critical lesion regions.

DISCUSSION: The proposed Swin-Tiny+ATT model exhibits strong potential for improving MRI-based classification of Alzheimer's Disease. The bidirectional spatial attention mechanism successfully directs the model's focus to relevant anatomical regions, contributing to higher precision and recall. Combined with data augmentation strategies, the approach mitigates class imbalance and enhances generalization. This work provides a promising deep learning framework to support early and accurate diagnosis of AD, with implications for clinical decision-making and personalized treatment planning.},
}

@article {pmid42039150,
year = {2026},
author = {Ouro, A and Ben-Dor, GA and Debasa-Mouce, M and Gulkarov, S and De Leon, J and Castro-Mosquera, M and Sobrino, T and Bougea, A and Reiss, AB},
title = {Monoclonal antibodies and small molecules: on the cutting edge of Alzheimer's disease therapy.},
journal = {Frontiers in cell and developmental biology},
volume = {14},
number = {},
pages = {1766762},
pmid = {42039150},
issn = {2296-634X},
abstract = {Alzheimer's disease (AD) remains a major global health challenge, with prevalence projected to increase dramatically in the coming decades and no effective treatments available. Current therapies offer only symptomatic relief, reinforcing the need for disease-modifying strategies targeting underlying pathogenic mechanisms. Advances in understanding amyloid-β (Aβ) and tau pathology have propelled the development of targeted interventions, particularly monoclonal antibodies (mAbs) and small-molecule therapeutics. Recent anti-Aβ antibodies, such as aducanumab, lecanemab, and donanemab, have demonstrated significant biological activity and reductions in amyloid burden, leading to regulatory approvals that represent important proof-of-concept milestones. However, these therapies face ongoing controversies related to modest clinical efficacy, accessibility, cost, and safety concerns. In parallel, small-molecule development has expanded beyond failed secretase inhibitors toward more refined mechanisms, including tau aggregation inhibition, kinase modulation, mitochondrial stabilization, and anti-inflammatory pathways. These compounds offer advantages in oral administration, blood-brain barrier penetration, and multi-target engagement. Together, mAbs and small molecules represent complementary therapeutic strategies addressing different aspects of AD pathophysiology. Their integration with emerging biomarkers, genetic profiling, and early diagnostic frameworks is driving a transition toward personalized and stage-specific treatment approaches. This review synthesizes current mechanistic insights, clinical evidence, and translational challenges of both modalities, highlighting how their convergence may shape the next-generation of AD therapeutics.},
}

@article {pmid42039285,
year = {2026},
author = {Chen, Y and Sun, X and Xi, Y and Luo, Z and Lai, H and Zhu, D and Zhang, Y and Xu, F and Li, J and Zhou, J and Ding, Y and Zhang, H},
title = {Pathology-directed drug delivery strategies: How to overcome blood-brain barrier for the treatment of brain diseases.},
journal = {Acta pharmaceutica Sinica. B},
volume = {16},
number = {4},
pages = {2250-2281},
pmid = {42039285},
issn = {2211-3835},
abstract = {Despite the different degrees of blood-brain barrier (BBB) damage in diverse brain diseases, it remains a formidable barrier that restricts most drugs from penetrating the brain. A comprehensive understanding and elucidation of the disease-specific changes of BBB in various brain pathologies are essential for directing the customized brain-targeted drug delivery systems, potentially improving cerebral delivery efficiency and therapeutic efficacy. Hence, this review compared anatomical and physiological changes of BBB under healthy and pathological states and discussed the effects of these changes on cerebral delivery efficiency. Thereafter, a particular emphasis was placed on the pathology-directed drug delivery strategies tailored to different brain diseases, including Alzheimer's disease, Parkinson's disease, multiple sclerosis, stroke, and brain tumors. By combining insights from cutting-edge studies and emerging technologies, we proposed forward-looking suggestions on future directions to brain-targeted drug delivery, thereby improving the therapeutic efficacy and accelerating the translation from preclinical attempts into clinical practice.},
}

@article {pmid42039533,
year = {2026},
author = {Lucciola, R and Herdy, JR and Vajaphattana, Y and Karbacher, L and Sabedot, TS and Cuoco, MS and Traxler, L and Kang, A and Reynolds, M and Jones, JR and Schafer, ST and Mertens, J and Gage, FH},
title = {RUNX1 and YY1 modulate neuronal fate and energy metabolism in Alzheimer's disease.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.04.13.716801},
pmid = {42039533},
issn = {2692-8205},
abstract = {Loss of neuronal identity and metabolic dysfunction are features of Alzheimer's disease (AD), yet the upstream-acting molecular drivers remain incompletely understood. By integrating multi-omics data from patient-derived induced neurons (iNs) and AD post-mortem human brains, we discovered that AD neurons express two master transcription factors (TFs), RUNX1 and YY1. While these TFs are primarily expressed during development where they play fundamental roles in cell fate determination and cellular bioenergetics, respectively, they can be reactivated in adult neurons in response to stress. To understand their functional role in AD neurons, we overexpressed RUNX1 or YY1 in aged iNs and found that the expression of each TF was sufficient to recapitulate two AD-associated features. Specifically, RUNX1 overexpression caused loss of neuronal fate, whereas YY1 overexpression regulated gene regulatory programs associated with metabolic dysfunction. Conversely, downregulation of either TF, in AD iNs, reinstated gene regulatory programs associated with a healthy mature neuronal phenotype. Together, these findings identify two transcriptional master regulators of the AD neuronal phenotype and establish a mechanistic foundation for further studying their role in the pathogenesis of AD and as putative therapeutical targets for the treatment of AD and age-associated neurodegeneration.},
}

@article {pmid42039828,
year = {2026},
author = {Li, Z and Xie, C and Pan, C},
title = {The oral-gut-brain axis: how periodontitis influence depression.},
journal = {Frontiers in microbiology},
volume = {17},
number = {},
pages = {1778744},
pmid = {42039828},
issn = {1664-302X},
abstract = {Depression has a high global prevalence and is a common mental-emotional disorder that severely jeopardizes human health. However, current treatment options remain limited, necessitating the exploration of novel pathological mechanisms and intervention targets. Recent studies indicate that periodontitis, as a prevalent chronic oral infectious disease, not only causes local microbial dysbiosis and inflammatory responses but may also influence central nervous system function through the "oral-gut-brain axis," thereby contributing to the pathogenesis and progression of neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, and multiple sclerosis, as well as neuropsychiatric disorders like depression. This review systematically examines the impact of periodontitis on oral microbiota and its subsequent translocation and colonization in the gut microbiota through pathways including swallowing and bloodstream circulation, ultimately leading to structural and functional dysregulation of the gut microbiota. The interaction between oral and gut microbiota can influence the brain through the "gut-brain axis," including disturbances in neurotransmitter metabolism, activation of systemic immune responses, and direct or indirect effects of bacterial metabolites (such as short-chain fatty acids, lipopolysaccharides, etc.) on the blood-brain barrier and neural function. This suggests that periodontal health management may serve as a novel strategy for the prevention and treatment of depression. This article further summarizes the potential of oral interventions for periodontitis (such as mechanical debridement and local/systemic antimicrobial therapy), microbiota modulation methods (such as probiotics, prebiotics, and fecal microbiota transplantation), and multidisciplinary collaborative comprehensive treatment strategies in improving microbial homeostasis and alleviating depressive symptoms. Finally, this paper points out the current research limitations in mechanistic details, causal relationships, and clinical translation, while envisioning the feasibility and prospects of developing personalized treatment strategies by targeting the "oral-gut-brain axis" in the future.},
}

@article {pmid42039925,
year = {2026},
author = {Lennon, MJ and Xu, Y and Thalamuthu, A and Mather, K and Sachdev, PS},
title = {Druggable genome-wide Mendelian randomization analysis identifies potential treatment targets in vascular dementia.},
journal = {Alzheimer's & dementia (New York, N. Y.)},
volume = {12},
number = {},
pages = {e70258},
pmid = {42039925},
issn = {2352-8737},
abstract = {BACKGROUND: There are currently no US Food and Drug Administration-approved treatments for vascular dementia (VaD). Genome-wide approaches have successfully identified druggable targets and treatments for various disorders. In this study, we performed druggable genome-wide two-sample Mendelian randomization (2SMR) analysis to identify possible treatment targets for VaD.

METHODS: 2SMR analyses were used to estimate the causal effects of druggable gene expression on VaD risk. The exposure variables were significant cis-expression quantitative trait loci (eQTLs) and cis-protein quantitative trait loci (pQTLs) in the cerebrospinal fluid (CSF), brain, and plasma. The main outcome variable was genetic VaD risk, based on the Mega Vascular Cognitive Impairment and Dementia Consortium genome-wide association study. 2SMR analysis examined the causal relationship between eQTLs/pQTLs and imaging markers of VaD. A phenome-wide 2SMR analysis explored the relationships between significant druggable genes and phenotype summary statistics derived from the UK Biobank. False discovery rate (FDR) P value corrections were applied to all analyses.

RESULTS: A total of 12,224 druggable genes were identified from the Drug-Gene Interaction Database (DGIdb) and associated papers. Of these, the 2SMR analysis identified four FDR-significant genes in the pQTL analysis, with none identified among the eQTLs. In the CSF, TOMM40 had a significant (P = 3.67E-36) effect on VaD outcomes as well as cerebral small vessel disease (cSVD), white matter hyperintensities (WMH; P = 0.0001) and fractional anisotropy (FA; P = 0.0028). In the brain, apolipoprotein E (APOE; P = 1.90E-54) was associated with VaD and three cSVD markers: WMH (P = 1.61E-06), FA (P = 0.0018), and mean diffusivity (P = 0.0244). ERAP1 (P = 0.0163), and SAA1-4 (P = 0.0163) showed weaker associations with VaD, did not show colocalization, and were not associated with cSVD imaging markers.

DISCUSSION: This study identified four potential drug targets for VaD, using a 2SMR analysis approach. Two genes, APOE and TOMM40, are well understood to be associated with both Alzheimer's disease and VaD, whereas the other two, ERAP1 and SAA1-4, are novel targets involved in immune system regulation and inflammation.},
}

@article {pmid42040886,
year = {2026},
author = {Fawad, A and van der Landen, SM and Tideman, P and van der Putten-Toorenburg, A and Butterbrod, E and Smith, R and van Westen, D and Calling, S and Midlöv, P and Mattsson-Carlgren, N and Borgström Bolmsjö, B and Stomrud, E and Nilsson, MH and Hansson, O and Sikkes, SAM and Palmqvist, S},
title = {Clinical staging in Swedish primary care using the Amsterdam Instrumental Activities of Daily Living Questionnaire.},
journal = {Alzheimer's & dementia (Amsterdam, Netherlands)},
volume = {18},
number = {},
pages = {e70344},
pmid = {42040886},
issn = {2352-8729},
abstract = {INTRODUCTION: We assessed the accuracy of the Amsterdam Instrumental Activities of Daily Living Questionnaire (A-IADL-Q) for clinical staging in Swedish primary care.

METHODS: Participants from the Swedish BioFINDER Primary Care study were included. Discriminative performance of the A-IADL-Q was evaluated using receiver operating curves. Multinomial and linear regression models assessed associations among A-IADL-Q scores, clinical stage, demographics, cognition, and comorbidities.

RESULTS: Among 623 patients, 148 (23.8%) had subjective cognitive decline (SCD), 274 (43.9%) mild cognitive impairment (MCI), and 201 (32.3%) dementia with a mean (standard deviation) age of 76.7 (7.3). The area under the curve (95% confidence interval) for discriminating between SCD versus MCI/dementia was 0.89 (0.86-0.91) and for SCD/MCI versus dementia 0.89 (0.87-0.92). Age (β = -0.25), Mini-Mental State Examination (β = 0.91) and Montreal Cognitive Assessment (β = 0.57), but no other demographics and comorbidities, were associated with the A-IADL-Q.

DISCUSSION: The A-IADL-Q may help primary care physicians determine clinical stage and shows promise for use to adequately refer patients to secondary or tertiary care.},
}

@article {pmid42041219,
year = {2024},
author = {Xie, P and Sun, C and Li, Y and Deng, Y and Xie, C},
title = {Clinical Study on Mesenchymal Stem Cell Factors Therapy for Alzheimer's Disease.},
journal = {Nigerian journal of clinical practice},
volume = {27},
number = {10},
pages = {1216-1220},
doi = {10.4103/njcp.njcp_561_24},
pmid = {42041219},
issn = {1119-3077},
abstract = {BACKGROUND: Alzheimer's disease (AD), characterized by cognitive decline, lacked effective cures. Mesenchymal stem cell (MSC) factors (MSCFs) offered a new approach by promoting brain tissue repair and modulating immune responses, presenting a promising alternative to AD treatment with minimal risks.

AIM: This study aimed to investigate the effects of MSCF on AD and to compare the effects with traditional MSC treatments.

METHODS: Sixty patients were divided into control and observation groups, with 30 cases in each group. The control group were injected intravenously with 10 mL of MSCs (5.0 × 10 9 L -1) plus 100 mL normal saline (once every 5 days for six consecutive treatments). The observation group received intramuscular injections of 0.5 mL (1 mL for the first dose) of MSCF (every other day for 15 consecutive treatments). Amyloid-β 42 (Aβ42) and Tau protein concentrations in cerebrospinal fluid were determined by ELISA pretreatment and at 1, 3, and 6 months' post-treatment. The Clinical Dementia Rating of AD patients was recorded at these intervals to evaluate treatment efficacy.

RESULTS: Aβ42 levels increased, and Tau protein levels decreased in both groups. The CDR score dropped post treatment. The total effective rate and clinical cure rate were 86.67% and 6.70% in the control group and 100% and 40% in the observation group, respectively. MSCF and MSCs uniquely impact AD.

CONCLUSION: MSCs contributed to damaged nerve cell repair, new nerve cell differentiation, and the participation of some dormant nerve cells in physiological activity. MSCF offered a small-dose, rapid, and safe treatment with simple operation.},
}

@article {pmid42041396,
year = {2026},
author = {Sumbria, RK and Boado, RJ},
title = {Brain Delivery of Antibody-Derived Biologicals for Alzheimer's Disease: An Updated Narrative Review.},
journal = {Antibodies (Basel, Switzerland)},
volume = {15},
number = {2},
pages = {},
doi = {10.3390/antib15020037},
pmid = {42041396},
issn = {2073-4468},
abstract = {Antibodies directed against β-amyloid (Aβ) have been developed for the treatment of Alzheimer's disease (AD). However, the in vivo central efficacy is reduced by the poor penetration of antibodies across the blood-brain barrier (BBB). In addition, these antibodies have been associated with adverse effects like amyloid-related imaging abnormalities. Thus, the development of new antibody-based therapies for AD with improved transport across the BBB may improve efficacy and reduce adverse effects. Antibodies targeting the BBB transferrin receptor (TfR) are able to cross the BBB through receptor-mediated transcytosis, producing a global distribution throughout the brain. Along the same line, bispecific antibodies directed to both the BBB TfR and Aβ showed enhanced brain uptake and pharmacological effects with diminished adverse side effects in experimental animal models of AD and in clinical trials. A generation of brain-penetrating fusion proteins targeting the BBB-TfR has been shown to represent novel treatments for AD, and this includes erythropoietin, tumor necrosis factor alpha inhibitors, neprilysin, somatostatin, oligonucleotides, and an antibody activating TREM2. The aim of this article is to review the progress made in the delivery of antibody-derived biologicals to the brain for AD, targeting the BBB-TfR.},
}

@article {pmid42041587,
year = {2026},
author = {Elias, A and Stern, S},
title = {Gene Editing Strategies for Neurological and Mental Disorders: Advances in Delivery, Methodology, and Clinical Translation.},
journal = {Cells},
volume = {15},
number = {8},
pages = {},
doi = {10.3390/cells15080720},
pmid = {42041587},
issn = {2073-4409},
mesh = {Humans ; *Gene Editing/methods ; *Nervous System Diseases/therapy/genetics ; *Mental Disorders/therapy/genetics ; *Genetic Therapy/methods ; Animals ; CRISPR-Cas Systems/genetics ; *Gene Transfer Techniques ; *Translational Research, Biomedical ; },
abstract = {Neurological and mental disorders are among the main causes of disability worldwide, affecting over three billion people and increasing the socioeconomic burden. Advances in molecular genetics and genome engineering have led to gene-targeted therapies that address root causes rather than just symptoms. This review covers current genome-editing tools, including CRISPR/Cas, base editing, and prime editing. The focus is on the benefits of gene editing in the central nervous system, where post-mitotic neurons allow lasting effects after a single treatment. It also discusses emerging delivery platforms such as viral vectors, nanoparticles, and exosome systems, as well as methods to bypass the blood-brain barrier. Recent clinical progress in spinal muscular atrophy, Parkinson's disease, Huntington's disease, and Alzheimer's disease is highlighted, with promising preclinical results for autism, bipolar disorder, epilepsy, and other neurogenetic conditions. The review concludes with regulatory issues, market trends, and ongoing clinical trials, underscoring the potential of gene therapies to transform disease management and provide long-term solutions.},
}

Humans
*Gene Editing/methods
*Nervous System Diseases/therapy/genetics
*Mental Disorders/therapy/genetics
*Genetic Therapy/methods
Animals
CRISPR-Cas Systems/genetics
*Gene Transfer Techniques
*Translational Research, Biomedical

@article {pmid42042055,
year = {2026},
author = {Jakobović, N and Kalinovčić, P and Borovec, J and Primožič, I and Hrenar, T},
title = {Quantum-Chemical Multiligand Simultaneous Docking of Three-Membered Rings in the Active Site of Butyrylcholinesterase.},
journal = {Current issues in molecular biology},
volume = {48},
number = {4},
pages = {},
doi = {10.3390/cimb48040395},
pmid = {42042055},
issn = {1467-3045},
support = {HRZZ-IP-2022-10-9525//Croatian science foundation/ ; },
abstract = {Alzheimer's disease is a progressive neurodegenerative disorder marked by declining cognitive function. While early-stage treatment focuses on acetylcholinesterase (AChE) inhibition, butyrylcholinesterase (BChE) activity increases as the disease progresses, contributing to cholinergic deficits and neuroinflammation. This shift in enzyme dominance presents a compelling rationale for developing BChE-specific inhibitors as a potential therapeutic avenue. This study explores small, three-membered rings, scaffolds offering potential for interaction with the enzyme's active site, as building blocks for novel BChE inhibitors. Employing a computational approach based on quantum-chemical multiligand simultaneous molecular docking, we virtually fitted these compounds into the BChE active site to predict binding affinity and key interactions. Our calculations extend beyond simple shape matching by incorporating accurate electronic properties, leading to more reliable predictions of binding strength and stability. The goal was not immediate identification of potent inhibitors, but a systematic assessment of how these rings interact with BChE. This foundational knowledge will inform the design and synthesis of larger, more complex molecules with enhanced binding affinity and selectivity, ultimately aiming to develop compounds to inhibit BChE activity and potentially slow Alzheimer's progression.},
}

@article {pmid42042094,
year = {2026},
author = {Allegra, P and Lodico, M and Migliazzo, C and Tarantino, D and Piccoli, T and Vanacore, N and Salemi, G and Maniscalco, L and Matranga, D},
title = {The Need for Standardized Data Collection to Improve Harmonization and Pooling of Information About Modifiable Risk Factors for Alzheimer's Diseases in Italian Clinical Studies: A Systematic Review.},
journal = {Geriatrics (Basel, Switzerland)},
volume = {11},
number = {2},
pages = {},
doi = {10.3390/geriatrics11020038},
pmid = {42042094},
issn = {2308-3417},
support = {"PNRR M6C2- Investimento 2.1 Valorizzazione e potenziamento della ricerca biomedica del SSN", grant number PNRRMAD-2022-12375822, CUP derivato: I75E22000550006-CUP Master ISS I55E22000560006//European Union-Next Generation EU/ ; },
abstract = {BACKGROUND/OBJECTIVES: At the international level, harmonized networks of dementia clinical studies are available, but Italian participation remains limited. This systematic review aims to define harmonization rules to facilitate the inclusion of Italian clinical studies in existing networks and to propose standardized data collection methods to enable comparison of the study results.

METHODS: A systematic review was conducted (January 2019-December 2024) to identify Italian clinical studies evaluating Alzheimer's disease and other dementias as outcomes. Eight modifiable risk factors were extracted: BMI, arterial hypertension, diabetes, dietary patterns, alcohol consumption, smoking habits, depressive symptomatology, and physical activity. WHO definitions and internationally accepted criteria were used as reference standards. Variable harmonization potential was assessed using the DataSHaPER methodology and classified as complete, partial, or impossible, considering information loss across studies.

RESULTS: Of 365 records identified, 18 studies met the inclusion criteria. Obesity assessed via BMI showed the highest harmonization potential (44% complete, 33% partial), along with dietary habits measured by food frequency questionnaires (44% complete). Diabetes and physical inactivity followed (33% complete), assessed through fasting glucose or pharmacological treatment and the IPAQ, respectively. Smoking habits classified as current, former, or never smokers were reported in 28% of studies. Depression (assessed by GDS or CES-D) and hypertension (blood pressure measurement or antihypertensive treatment) showed complete harmonization in only 22% of studies.

CONCLUSIONS: Italian studies show substantial limitations in the harmonization of modifiable risk factor data for Alzheimer's disease, mainly due to heterogeneous and non-standardized data collection methods, highlighting the need for uniform research protocols.},
}

@article {pmid42042095,
year = {2026},
author = {Durrani, S and Mussawar, M and Alaverdashvili, M},
title = {Impact of Comprehensive Geriatric Assessments on Dementia Care.},
journal = {Geriatrics (Basel, Switzerland)},
volume = {11},
number = {2},
pages = {},
doi = {10.3390/geriatrics11020039},
pmid = {42042095},
issn = {2308-3417},
abstract = {Introduction: According to the Alzheimer Society of Canada, over 770,000 people in Canada are living with dementia. This number is expected to rise to nearly 1 million people by 2030. Although the provision of team-based interprofessional assessment in gerontological care is critical for the early detection and prevention of dementia, its planning and delivery can be a challenge. In Saskatchewan, previous assessments have identified significant gaps between actual and best practices in dealing with this medical condition. The emergence of Geriatric Services Resource Teams (GSRTs), which apply an innovative, team-based model to improve the diagnosis and care of older adults with complex health practices, can be proven beneficial in this regard. The purpose of this study is to compare the efficacy of the care provision process between a GSRT and a traditional medical care channel (i.e., primary health) with respect to dementia patients. Methods: A retrospective patient chart review was conducted by collecting data from a large Primary Care practice (n = 90) and the GSRT in Regina (n = 75). Collected data included information on patient demographics and treatment, and the diagnosis process itself. Results: While demographic characteristics between patient groups were similar, significant differences (p < 0.05) were found in the involvement of pharmacy and other healthcare professionals, prescriptions for memory loss, and in who made the diagnosis. Moreover, although the dementia diagnosis was usually made first in Primary Care, further clarification of the type of dementia, counseling of diagnosis, review of medication, and assessment of functions and social supports were better managed in the GSRT group. Discussion: The use of Geriatric Services Resource Teams is a relatively new concept in Saskatchewan. As these teams are established, initial results show that their role in complex care management has beneficial outcomes for dementia patients.},
}

@article {pmid42042200,
year = {2026},
author = {Xu, ZH and Zou, ZB and Wang, CX and Li, C and Yang, XW and Wang, JS},
title = {Anti-Neuroinflammatory Naphtho-γ-Pyrones from a Deep-Sea-Derived Fungus Aspergillus niger 3A00562.},
journal = {Marine drugs},
volume = {24},
number = {4},
pages = {},
doi = {10.3390/md24040125},
pmid = {42042200},
issn = {1660-3397},
support = {22177143//National Natural Science Foundation of China/ ; },
mesh = {Animals ; Zebrafish ; *Pyrones/pharmacology/chemistry/isolation & purification ; *Aspergillus niger/chemistry ; *Anti-Inflammatory Agents/pharmacology/chemistry/isolation & purification ; Molecular Docking Simulation ; Alzheimer Disease/drug therapy ; Mice ; Oxidative Stress/drug effects ; Nitric Oxide Synthase Type II/metabolism ; Disease Models, Animal ; Microglia/drug effects ; Cell Line ; Aquatic Organisms ; Inflammation/drug therapy ; Reactive Oxygen Species/metabolism ; },
abstract = {Inhibition of inflammation and oxidative stress is increasingly recognized as a promising therapeutic strategy for neurodegenerative diseases. In this study, we isolated two new dimeric naphtho-γ-pyrone (aS)-fonsecinones B and D (1 and 2) and 14 known compounds (3-16) from the deep-sea-derived fungus Aspergillus niger 3A00562. Their structures were unambiguously determined through integrated physicochemical and spectroscopic analyses. Screening for neuroinflammatory inhibitors using a BV2 microglial cell model identified TMC 256 A1 (10) as the most potent candidate. Compound 10 significantly suppressed LPS-induced inflammation in BV2 cells without cytotoxicity. It concurrently inhibited LPS-triggered ROS overproduction and neutrophilic infiltration in zebrafish. Subsequent proteomics revealed that 10 targets NOS2 to modulate Alzheimer's disease (AD)-associated pathways and the KEAP1-NRF2 axis. Molecular docking and dynamics simulations demonstrated that 10 occupies the NOS2 heme-binding pocket, thereby preventing dimerization and inhibiting enzymatic activity. Finally, 10 ameliorated locomotor deficits in an AD zebrafish model. Collectively, these findings highlight compound 10 as a candidate compound for preventing inflammatory and oxidative stress damage during treatment of neurodegenerative diseases, particularly AD.},
}

Animals
Zebrafish
*Pyrones/pharmacology/chemistry/isolation & purification
*Aspergillus niger/chemistry
*Anti-Inflammatory Agents/pharmacology/chemistry/isolation & purification
Molecular Docking Simulation
Alzheimer Disease/drug therapy
Mice
Oxidative Stress/drug effects
Nitric Oxide Synthase Type II/metabolism
Disease Models, Animal
Microglia/drug effects
Cell Line
Aquatic Organisms
Inflammation/drug therapy
Reactive Oxygen Species/metabolism

@article {pmid42042246,
year = {2026},
author = {Abdullah, and Fatima, Z and Ruiz, MJT and Espinosa-Sosa, O and Sánchez-Mejorada, CG and Téllez, RQ and Rodríguez, JLO and Sidorov, G},
title = {Explainable Patient-Level Cognitive Impairment Screening via Temporal, Semantic, and Psycholinguistic Multimodal AI.},
journal = {Journal of Intelligence},
volume = {14},
number = {4},
pages = {},
doi = {10.3390/jintelligence14040066},
pmid = {42042246},
issn = {2079-3200},
abstract = {Early diagnosis of cognitive decline is vital for timely treatment of mild cognitive impairment (MCI) and Alzheimer's disease (AD), yet standard clinical assessments often miss subtle longitudinal language changes. We propose a hierarchical hybrid intelligence framework integrating long-context language modeling, temporal progression, semantic graph reasoning, psycholinguistic biomarkers, and contrastive progression learning to classify patient states (Normal, MCI, AD) from longitudinal electronic health record (EHR) notes. The model was trained on 4500 patients and 68,000 clinical notes from Medical Information Mart for Intensive Care III (MIMIC-III) and externally validated on the Medical Information Mart for Intensive Care IV (MIMIC-IV) clinical notes dataset (5200 patients, 72,000 notes). Inputs combined Biomedical and Clinical Bidirectional Encoder Representations from Transformers (BioClinicalBERT) embeddings, Bidirectional Long Short-Term Memory (Bi-LSTM) temporal encodings, Graph Sample and Aggregate (GraphSAGE)-based Unified Medical Language System (UMLS) concept graphs, and psycholinguistic vectors (lexical diversity, grammatical complexity, discourse coherence). On the MIMIC-III hold-out set, the model achieved 99.999% accuracy, a macro F1-score of 0.999, a Receiver Operating Characteristic Area Under the Curve (ROC AUC) of 0.999, and a temporal stability variance of 0.0008. Monte Carlo cross-validation (10,000 folds) yielded 99.997±0.003% accuracy and 0.999±0.001 macro F1. Feature ablation confirmed distinct gains from temporal, semantic, and psycholinguistic modules, improving performance by 1.1% over text-only baselines. Cross-cohort zero-shot testing on MIMIC-IV showed strong generalization with minimal decline in macro F1 and balanced accuracy. Explainability analyses, such as SHapley Additive exPlanations (SHAP) token/concept attribution, attention maps, counterfactual perturbations, and psycholinguistic importance, revealed clinically interpretable markers, such as pronoun overuse, reduced lexical diversity, and syntactic simplification, as predictors of decline. Our framework supports scalable, non-invasive early screening in a variety of healthcare settings by providing longitudinally stable predictions.},
}

@article {pmid42043712,
year = {2026},
author = {Khozani, MS and Palizvan, M and Mosayebi, G and Ganji, A and Ghazavi, A},
title = {Chitosan-curcumin nanoparticles: a potential nano-therapeutic for cognitive restoration in a streptozotocin-induced rat model of Alzheimer's disease.},
journal = {Inflammopharmacology},
volume = {},
number = {},
pages = {},
pmid = {42043712},
issn = {1568-5608},
abstract = {BACKGROUND: Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline and memory impairment, with no definitive cure currently available. Neuroinflammation, oxidative stress, and amyloid-beta accumulation play central roles in disease progression. While curcumin shows therapeutic promise, its clinical efficacy is limited due to poor bioavailability. This study investigates the neuroprotective effects of chitosan-curcumin nanoparticles in a streptozotocin (STZ)-induced rat model of AD, focusing on cognitive performance, hippocampal integrity, and molecular markers of neurodegeneration.

METHODS: Sixty male Wistar rats were randomly divided into five groups: control, AD, AD + chitosan, AD + curcumin, and AD + chitosan-curcumin. AD was induced via intraventricular injection of STZ (3 mg/kg). Two weeks' post-induction, cognitive function was assessed using the Morris water maze (MWM). At the end of the treatment period, oxidative stress parameters, inflammatory cytokines, and gene expression levels (IL-1β, IL-6, IL-10, NRF2, PPARγ, BDNF) were measured via real-time PCR. Data were analyzed using one-way ANOVA with Tukey's post hoc test (p < 0.05).

RESULTS: Rats treated with chitosan-curcumin nanoparticles exhibited significantly improved memory and learning compared to all other groups (p < 0.001). There was a marked downregulation of IL-1β and IL-6, along with increased expression of NRF2, PPARγ, and BDNF (p < 0.05). Histological analysis confirmed reduced neuronal damage and increased neuronal density. Chitosan-curcumin nanoparticles demonstrated potent neuroprotective effects, enhancing cognitive performance, reducing inflammation and oxidative stress, and preserving neuronal structure.

CONCLUSION: These multifaceted effects highlight the therapeutic potential of CS-CUR nanoparticles in targeting the core pathological mechanisms of AD. Future studies should focus on long-term safety and efficacy assessments, dose-response optimization, and mechanistic pathway analyses to further elucidate the neuroprotective actions of CS-CUR nanoparticles. Additionally, translational and clinical investigations are warranted to validate the therapeutic potential of this nanocarrier system for Alzheimer's disease management.},
}

@article {pmid42043831,
year = {2026},
author = {Farrell, C and Saini, F and Beidas, MM and Ryan, NS and Strydom, A and Wiseman, FK},
title = {Use of anti-amyloid-β monoclonal antibodies in persons with Down syndrome Alzheimer's disease.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {4},
pages = {e71404},
doi = {10.1002/alz.71404},
pmid = {42043831},
issn = {1552-5279},
support = {UKDRI-1211//UK Dementia Research Institute through UK DRI Ltd, principally funded by the UK Medical Research Council/ ; UKDRI-1010//UK Dementia Research Institute through UK DRI Ltd, principally funded by the UK Medical Research Council/ ; UKDRI-TAP23∖12//UK Dementia Research Institute through UK DRI Ltd, principally funded by the UK Medical Research Council/ ; AS-PhD-19a-007/ALZS_/Alzheimer's Society/United Kingdom ; MB2020∖100003//Rosetrees Trust/ ; 2021B#2083//the Jérôme Lejeune Foundation/ ; MR/S011277/1/MRC_/Medical Research Council/United Kingdom ; MR/S005145/1/MRC_/Medical Research Council/United Kingdom ; MR/R024901/1/MRC_/Medical Research Council/United Kingdom ; //National Institute for Health and Care Research/ ; //NIHR University College London Hospitals Biomedical Research Centre (BRC), NIHR Maudsley BRC/ ; //UCL Neurogenetic Therapies Programme/ ; //funded by the Sigrid Rausing Trust/ ; NC/S001298/1/NC3RS_/National Centre for the Replacement, Refinement and Reduction of Animals in Research/United Kingdom ; ARUK-SRF2018A-001//Alzheimer's Research UK/ ; ARUK-SRFEXT2022-001//Alzheimer's Research UK/ ; },
mesh = {Humans ; *Down Syndrome/complications ; *Alzheimer Disease/drug therapy/complications/immunology ; *Amyloid beta-Peptides/immunology ; *Antibodies, Monoclonal/therapeutic use ; Blood-Brain Barrier ; Antibodies, Monoclonal, Humanized/therapeutic use ; },
abstract = {INTRODUCTION: The recent development and licensing of anti-amyloid-β monoclonal antibodies for the treatment of early-stage Alzheimer's disease have significantly shifted the clinical landscape. However, current use recommendations preclude the administration of these new drugs to persons who have Down syndrome.

METHODS: This narrative review considers the ethical and biological factors relating to the administration of anti-amyloid-β monoclonal antibody therapies to persons who have Down syndrome. Literature was selected based on relevance.

RESULTS: Here, we discuss the current understanding of Down syndrome Alzheimer's disease, and how this informs potential benefits and risks of treatment with anti-amyloid-β monoclonal antibodies.

DISCUSSION: The blood-brain barrier and immune system differ in persons with Down syndrome, and cerebral amyloid angiopathy is elevated compared to late-onset Alzheimer's disease. Thus, side-effect risks from anti-amyloid-β monoclonal antibodies are likely to be elevated. Further research is needed to facilitate the treatment of persons with Down syndrome with these new therapies.},
}

Humans
*Down Syndrome/complications
*Alzheimer Disease/drug therapy/complications/immunology
*Amyloid beta-Peptides/immunology
*Antibodies, Monoclonal/therapeutic use
Blood-Brain Barrier
Antibodies, Monoclonal, Humanized/therapeutic use

@article {pmid42043884,
year = {2026},
author = {Bonpandi, E and John, C and Arumugam, P},
title = {Synthesis, structural elucidation, DNA binding, cleavage, cholinesterase inhibitory activity of metal complexes of novel 2,2'-bipyridyl derivative.},
journal = {Nucleosides, nucleotides & nucleic acids},
volume = {},
number = {},
pages = {1-34},
doi = {10.1080/15257770.2026.2659226},
pmid = {42043884},
issn = {1532-2335},
abstract = {To achieve efficient cholinesterase inhibitory activity of metal(II) complexes of Cu(II), Ni(II), Co(II), and Zn(II) with 2,2'-bipyridyl framework [M-L] (L = 2,2'-bipyridyl derivative containing an aromatic center and an e[-]-withdrawing -NO2 group) was developed. The structural characteristics were identified through spectroscopic and analytical studies. The antibacterial activity of the produced ligand and metal(II) complexes against bacteria and fungi was evaluated. The synthesized metal(II) complexes ability to fragment DNA has been studied on pUC 18 DNA using agarose gel electrophoresis. The copper(II) complex (Kb=4.11 × 10[5] M[-1]) is stronger binding affinity for DNA than ethidium bromide (EB) (Kb=3.3 × 10[5] M[-1]) and metal(II) complexes. The chemically produced 2,2'-bipyridyl derivative had the strongest inhibitory effects against acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) with IC50 values that were less than the standard compounds (0.34 and 3.42 µM, respectively). Our research results could aid in the creation of novel drug molecules, especially for the treatment of neurological conditions like Alzheimer's disease and neurological disorders occurring through diabetes.},
}

@article {pmid42043894,
year = {2026},
author = {Dendooven, A and Vandendriessche, A and Koshy, PJ and Timmermans, F and Speeckaert, M and Kint, N and Van Aelst, L and Vekemans, MC and Meuleman, N and Pouleur, AC and Bondue, A and Droogmans, S and Debonnaire, P and De Bleecker, J and Van Craenenbroeck, A and Gallardo, R and Schymkowitz, J and Rousseau, F and Impens, F and Devos, S and Delforge, M},
title = {Belgian recommendations for tissue diagnosis of amyloidosis.},
journal = {Acta clinica Belgica},
volume = {},
number = {},
pages = {1-14},
doi = {10.1080/17843286.2026.2660739},
pmid = {42043894},
issn = {2295-3337},
abstract = {BACKGROUND: Amyloidosis is a disorder caused by the extracellular deposition of misfolded protein fibrils, leading to organ dysfunction. Diagnosis remains challenging due to non-specific clinical presentations and the diversity of amyloid subtypes. Accurate identification of the amyloid precursor protein is key for prognostication and treatment strategy.

OBJECTIVES: This document aims to provide practical recommendations for the tissue diagnosis of amyloidosis within the Belgian healthcare context. It targets clinicians managing amyloidosis patients and pathologists evaluating biopsies with suspected amyloid deposits.

METHODS: A structured PubMed search ('amyloidosis AND biopsy AND stain*'; 'amyloidosis AND mass spectro*') was conducted in August 2025. After exclusion of case reports, preclinical studies, and Alzheimer-related articles, 298 publications were reviewed. Recommendations were formulated based on available evidence and discussed among Belgian clinical and pathology experts.

RESULTS: Key recommendations emphasize that tissue biopsies remain essential for amyloidosis diagnosis and typing. Congo red staining with birefringence and fluorescence confirmation is required. Immunohistochemistry and immunofluorescence are first-line subtyping tools, while mass spectrometry serves as a reference method when results remain inconclusive. Centralization of complex analyses in experienced centres is encouraged.

CONCLUSIONS: These recommendations promote standardized, early and accurate tissue diagnosis of amyloidosis in Belgium, supporting optimal patient management and harmonization of diagnostic practices across institutions.},
}

@article {pmid42030370,
year = {2026},
author = {Panda, SR and Soni, U and Panja, P and Rajdev, B and Singh, M and Kundu, S and Ranade, A and Pawar, SD and Acharya, R and Naidu, VGM},
title = {Modulation of Mitochondrial Dynamics by Loganic Acid Ameliorates Alzheimer's Disease Pathology: Evidence from In Vitro and In Vivo Studies.},
journal = {ACS chemical neuroscience},
volume = {},
number = {},
pages = {},
doi = {10.1021/acschemneuro.6c00012},
pmid = {42030370},
issn = {1948-7193},
abstract = {Alzheimer's disease (AD) is the most common neurodegenerative disorder in the elderly, which refers to forgetting facts and experiences. Apart from being a classical neuropathological hallmark, AD is connected with pronounced mitochondrial fragmentation, although the exact contribution of mitochondrial dynamics in AD progression is poorly defined. Therefore, this study is aimed at investigating the role of loganic acid (LGA) in mitochondrial dynamics, hippocampal plasticity, and cognitive deficits in the scopolamine (SC)-induced cognitive impairment model. The results showed significant decline of p-Drp1 protein and elevation of Mfn2 proteins in LGA-treated SC-induced mice, indicating reduced mitochondrial fragmentation and restoration of mitochondrial dynamics. In addition, LGA treatment promotes the reduction of fragmented and spherical-shaped mitochondria in SC-induced mice. LGA treatment alleviated reactive oxygen species (ROS) production and elevated mitochondrial membrane potential, reducing neurodegeneration in SC mice. Moreover, the decline of inflammatory cytokines (TNF-α and IL-1β) and downregulation of NF-kB expression in LGA-treated SC-induced mice suggested improved neuronal health. In parallel, LGA also increased the regulation of the cytoskeleton within neuronal dendrites, synaptic plasticity, and neuronal dendrites outgrowth, which was validated with increased expression of MAP2. In conclusion, the present study findings suggest that LGA exerts neuroprotection via preserving the mitochondrial ultrastructure and modulating the mitochondrial dynamics. All of these changes further restore neuronal cell density and myelination, leading to the mitigation of neurodegeneration, and restore cognitive deficits and spatial memory in SC-induced C57BL/6 mice.},
}

@article {pmid42031084,
year = {2026},
author = {Hernández, A and Illán, IA and Ramírez, J and Segovia, F and Martínez-Murcia, FJ and Levin, J and Górriz, JM and , },
title = {Robust validation of neuroimaging and clinical models via the SAR method: A case study based on the ADNI dataset.},
journal = {NeuroImage},
volume = {333},
number = {},
pages = {121917},
doi = {10.1016/j.neuroimage.2026.121917},
pmid = {42031084},
issn = {1095-9572},
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline and substantial brain atrophy. Early and accurate prediction of disease progression and staging is crucial for timely intervention and effective treatment planning. Previous studies, including those based on artificial intelligence techniques, have employed neuroimaging, biomarkers and clinical data to model AD progression; however, many of these approaches rely on strong parametric assumptions or lack robust statistical guarantees regarding model validity. To bridge this gap, this study proposes a novel framework for validating predictive and staging models of disease using a statistically agnostic methodology. The objective is to take the advantages of an unconventional method for robust validation of ML models related to AD. Validation is performed using the Statistical Agnostic Regression (SAR) methodology applied to the Alzheimer's Disease Neuroimaging Initiative (ADNI) dataset. The method tests for a linear relationship by resampling and estimating an upper bound on the expected risk (R) via a Bayesian bound under the worst-case scenario. The SAR power assesses the likelihood of detecting a true linear relationship using the test statistic R, via Monte Carlo simulations under the null distribution. Three predictive models related to structural neuroimaging are assessed: one for the Mini Mental State Examination (MMSE) score, another for the concentration of amyloid beta 1-42 protein in the cerebrospinal fluid, and a third for age. In addition, a model for staging based on Alzheimer's-related clinical groups is explored through the joint analysis of segmented gray matter and white matter images. The findings indicate that the SAR methodology not only facilitates robust validation of predictive ML models related to neuroimaging and AD but also enables an effective staging of the AD continuum. This SAR-proposed framework opens new perspectives for the validation of ML models for early diagnosis and provides a solid foundation for future research in computational neuroscience.},
}

@article {pmid42033099,
year = {2026},
author = {Luo, QH and Li, F and Yang, L and Pan, HQ and Zhu, WP and Hu, P and Tao, CM and Yin, M and Zhang, S and Liao, QY and Chen, ZH and Shu, HX and Zhu, XY and Yan, TF and Liu, X and Tu, JL and Zhu, XG},
title = {Endothelial NAD[+] depletion drives vascular senescence and neuroinflammation via mtDNA-cGAS/STING-CD38 signaling in Alzheimer's disease.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {4},
pages = {e71423},
pmid = {42033099},
issn = {1552-5279},
support = {82501463//National Natural Science Foundation of China/ ; 82260278//National Natural Science Foundation of China/ ; 20232BAB216047//Jiangxi Provincial Natural Science Foundation/ ; 20242BAB25478//Jiangxi Provincial Natural Science Foundation/ ; 20242BAB26136//Jiangxi Provincial Natural Science Foundation/ ; 20242BAB20383//Jiangxi Provincial Natural Science Foundation/ ; 2023M741521//China Postdoctoral Science Foundation/ ; },
mesh = {Animals ; *NAD/deficiency/metabolism ; *Alzheimer Disease/metabolism/pathology ; Mice ; *DNA, Mitochondrial/metabolism ; Signal Transduction ; *Endothelial Cells/metabolism ; *Nucleotidyltransferases/metabolism ; Membrane Proteins/metabolism ; *Neuroinflammatory Diseases/metabolism ; Mice, Transgenic ; Cellular Senescence ; Humans ; Disease Models, Animal ; Mitochondria/metabolism ; STING Protein ; Cyclic Guanosine Monophosphate-Adenosine Monophosphate Synthase ; Niacinamide/analogs & derivatives ; Pyridinium Compounds ; },
abstract = {BACKGROUND: Endothelial dysfunction has emerged as early and pivotal event in Alzheimer's disease (AD), yet the molecular mechanisms linking vascular aging to neuroinflammation remain elusive.

METHODS: We used APP/PS1 mice and amyloid beta (Aβ)-challenged brain endothelial cells (BECs) to understand the mechanisms of nicotinamide adenine dinucleotide (NAD[+]) deficiency, and its relationship with endothelial senescence and neuroinflammation in AD pathology. Nicotinamide riboside supplementation was administered to APP/PS1 mice to determine whether restoration of NAD[+] homeostasis mitigates AD-related vascular and inflammatory pathology.

RESULTS: NAD[+] deficiency induced voltage-dependent anion channel 1 (VDAC1) oligomerization, mitochondrial DNA (mtDNA) leakage, and cGAS/STING-IRF3 activation, promoting endothelial senescence and SASP production with NAD[+]-consuming enzyme CD38 upregulation. Senescent BECs triggered IL-6-dependent microglial activation. NR treatment restored mitochondrial integrity, suppressed cGAS-STING signaling, and reduced neuroinflammation, improving vascular function and cognition.

DISCUSSION: Aβ-driven NAD[+] deficiency initiates a VDAC1-mtDNA-cGAS/STING cascade that promotes endothelial senescence and neurovascular inflammation in AD pathology, and amplifies neuroinflammation through BEC-microglia crosstalk, highlighting NAD[+] restoration as a promising AD therapeutic strategy.},
}

Animals
*NAD/deficiency/metabolism
*Alzheimer Disease/metabolism/pathology
Mice
*DNA, Mitochondrial/metabolism
Signal Transduction
*Endothelial Cells/metabolism
*Nucleotidyltransferases/metabolism
Membrane Proteins/metabolism
*Neuroinflammatory Diseases/metabolism
Mice, Transgenic
Cellular Senescence
Humans
Disease Models, Animal
Mitochondria/metabolism
STING Protein
Cyclic Guanosine Monophosphate-Adenosine Monophosphate Synthase
Niacinamide/analogs & derivatives
Pyridinium Compounds

@article {pmid42033410,
year = {2026},
author = {Gu, X and Terebuh, P and Xu, R and Kaelber, DC and Davis, PB},
title = {Age-related macular degeneration and dementia: Association through pathogenesis or visual impairment?.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261438849},
doi = {10.1177/13872877261438849},
pmid = {42033410},
issn = {1875-8908},
abstract = {BackgroundStudies suggest a link between blindness, age-related macular degeneration (AMD), and dementia risk, but whether this stems from AMD pathology or blindness remains unclear. This study examines the relationship between AMD and dementia.ObjectiveTo evaluate the association between AMD and 5-year dementia risk in non-blind patients.MethodsThis retrospective cohort study used TriNetX to compare non-blind patients with exudative AMD (n = 35,021) and non-exudative AMD (n = 96,809) to those without AMD (n = 1,801,879) for five-year dementia risk. Blind (n = 90,615) and non-blind (n = 800,737) patients were compared. Cohorts were propensity-matched for confounding factors.ResultsNon-blind AMD patients had decreased Alzheimer's disease risk, while blindness showed a strong positive association. Exudative AMD had HR of 0.84 (95% CI = [0.72, 0.97]), non-exudative AMD had HR of 0.95 (95% CI = [0.87, 1.04]), but blindness increased Alzheimer's disease risk (95% HR = 1.29, CI = [1.17, 1.41]).ConclusionsThese findings suggest that previously reported associations between AMD and dementia may be partially mediated by visual impairment. The modest reduction in dementia risk in non-blind AMD patients may reflect differences in healthcare utilization or treatment exposure among AMD patients.},
}

@article {pmid42033565,
year = {2026},
author = {Ishii, K},
title = {Brain PET in the era of anti-amyloid-β antibody therapy for Alzheimer disease.},
journal = {Japanese journal of radiology},
volume = {},
number = {},
pages = {},
pmid = {42033565},
issn = {1867-108X},
abstract = {Here the current and emerging roles of brain positron emission tomography (PET) in Alzheimer's disease (AD) in the era of anti-amyloid-β antibody therapy, with a focus on clinical applications, methodological considerations, and future perspectives were reviewed. A narrative review of the literature on PET imaging in AD, including FDG-PET, amyloid PET, and tau PET, was conducted with particular emphasis on their clinical utility in diagnosis, and disease monitoring. Relevant guidelines, including appropriate use criteria and Japanese clinical guidelines, were also reviewed. FDG-PET provides valuable information for the differential diagnosis of neurodegenerative dementias based on characteristic hypometabolic patterns, although its role remains supportive due to the lack of direct assessment of molecular pathology. Amyloid PET enables noninvasive visualization of cerebral amyloid-β deposition and has become essential for confirming eligibility for anti-amyloid therapies. Standardized use criteria and interpretation guidelines are critical for appropriate clinical implementation. Quantitative approaches, such as standardized uptake value ratios (SUVRs) and the Centiloid scale, improve comparability across studies and institutions. Tau PET reflects neurofibrillary pathology and correlates with disease severity and progression, with increasing relevance for patient stratification. In addition, recent advances in high-resolution dedicated brain PET systems and artificial intelligence-based image analysis are expected to enhance diagnostic performance and workflow efficiency. In the era of disease-modifying therapy, brain PET imaging has become integral to the clinical management of AD. Amyloid PET is indispensable for treatment eligibility, while tau PET provides complementary information on disease stage and prognosis. Ongoing technological and methodological advancements will further expand the role of PET imaging in precision medicine for dementia.},
}

@article {pmid42028071,
year = {2026},
author = {Sun, X and Yang, L and Wang, X},
title = {Traditional Chinese Medicine for Alzheimer's Disease: Current Evidence and Chemometric Approaches for Multi-Target Evaluation.},
journal = {Neuropsychiatric disease and treatment},
volume = {22},
number = {},
pages = {590661},
pmid = {42028071},
issn = {1176-6328},
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder for which there is currently no therapy that can fundamentally change the disease course. The limitations of single-target drugs have led the scientific community to turn to multi-target intervention strategies. In this context, traditional Chinese medicine (TCM) demonstrates potential in addressing the complex pathology of AD due to its "multi-component, multi-target, multi-pathway" overall regulatory characteristics. This review systematically reviews the current research status of TCM in the treatment of AD, with a particular focus on the evidence of its effects through multiple mechanisms such as reducing Aβ deposition, inhibiting excessive phosphorylation of Tau protein, regulating the cholinergic system, and alleviating neuroinflammation. Additionally, this article highlights how to utilize the "spectral efficacy relationship" combined with chemometrics methods (such as multiple regression, partial least squares regression, artificial neural networks, etc) to establish quantitative correlations between TCM chemical components and efficacy/clinical endpoints, thereby providing a methodological framework for evaluating the synergistic effects of TCM's multi-component interactions. The article also summarizes the evidence grades of currently commonly used TCM preparations in clinical practice and points out that future research needs to continuously deepen in areas such as standardized clinical endpoints, strict trial design, systematic safety assessment, and data-driven efficacy analysis. This review aims to provide theoretical references and research directions for integrating the holistic view of TCM with modern system analysis methods and promoting the development of multi-target treatment strategies for AD.},
}

@article {pmid42025825,
year = {2026},
author = {Liu, S and Yang, C and Zhang, N and Xiang, L and Li, F and Qi, L and Xu, X},
title = {AXL prevents amyloid-β-induced microglial ferroptosis by sustaining SLC2A3-mediated mitochondrial respiration.},
journal = {Pharmacological research},
volume = {},
number = {},
pages = {108203},
doi = {10.1016/j.phrs.2026.108203},
pmid = {42025825},
issn = {1096-1186},
abstract = {Dysregulated iron metabolism is a pivotal driver of Alzheimer's disease (AD). Excess iron promotes Aβ aggregation and tau hyperphosphorylation, thereby accelerating disease progression. Serving as the primary iron reservoir in the central nervous system, microglia are intrinsically susceptible to ferroptosis, thereby amplifying neurotoxicity to neighboring neurons. While plaque-associated receptors (e.g., TREM2, AXL, MERTK) govern microglial responses, their precise contribution to metabolic susceptibility to ferroptosis remains elusive. Here, we identify the receptor tyrosine kinase AXL as a critical metabolic safeguard against Aβ-induced ferroptosis in microglia. Mechanistically, our findings indicate that, under our experimental conditions, oAβ exposure is associated with downregulation of AXL in microglia, thereby impairing SLC2A3-dependent glucose uptake and mitochondrial ATP production, which ultimately increases ferroptotic vulnerability. Moreover, through an optimized surface plasmon resonance imaging (SPRi) screening approach, we identified the FDA-approved drug levothyroxine (L-T4) as a potent AXL agonist. L-T4 treatment restores microglial homeostasis, inhibits Aβ-induced ferroptosis, and ameliorates neuropathology in vivo. These findings establish AXL as a novel metabolic safeguard in microglia and highlight L-T4 as a promising therapeutic strategy for AD and other ferroptosis-related disorders via drug repurposing.},
}

@article {pmid42025961,
year = {2026},
author = {Hajibandeh, S and Tao, YA and Hsieh, MH and Liu, HG and Cheng, YF and Lee, KH and Hsieh, SY and Lu, CH},
title = {Semaglutide for obesity management: A narrative review of efficacy, safety, and future directions.},
journal = {Journal of the American Pharmacists Association : JAPhA},
volume = {},
number = {},
pages = {103117},
doi = {10.1016/j.japh.2026.103117},
pmid = {42025961},
issn = {1544-3450},
abstract = {BACKGROUND: Glucagon-like peptide-1 receptor agonists (GLP-1 RAs), particularly semaglutide, have demonstrated substantial efficacy for glycemic control and weight management and are increasingly prescribed across diverse populations. Rapid expansion of indications, formulations, and real-world use has outpaced comprehensive evaluation of long-term safety, tolerability, and adherence, raising important concerns for clinical practice.

OBJECTIVES: This narrative review aims to synthesize current evidence on the efficacy and safety profile of semaglutide, with a focus on adverse events, treatment persistence, perioperative considerations, and use in special populations, to support clinical decision-making and pharmacist-led patient care.

METHODS: A review of clinical trials, observational studies, pharmacovigilance reports, regulatory communications, and professional guidelines was conducted. Evidence was drawn from randomized controlled trials, post-marketing safety reports, systematic reviews, and relevant clinical and regulatory documents.

RESULTS: From 1525 records, 34 studies and reports were included. Clinical trials consistently demonstrated meaningful weight reduction with semaglutide. Evidence regarding acute pancreatitis remains limited, although cases have been reported in clinical trials and postmarketing safety analyses. Evidence regarding suicidal ideation associated with semaglutide is mixed, with some analyses suggesting potential safety signals while others report no increased risk. Recent multi society clinical guidelines have addressed perioperative management of GLP-1 RAs, generally supporting individualized perioperative assessment. Emerging literature also examines semaglutide use in special populations, including patients with Alzheimer disease and individuals following bariatric surgery, although long-term neurologic and post-bariatric safety outcomes remain incompletely characterized.

CONCLUSIONS: Semaglutide represents an important therapeutic option for chronic weight management. As clinical use expands, continued evaluation of long-term safety, tolerability, and treatment persistence will be important. Pharmacists play a key role in counseling patients, monitoring adverse effects, supporting adherence, and contributing to multidisciplinary obesity care.},
}

@article {pmid42026254,
year = {2026},
author = {Nakagawa, T and Xie, JL and Park, K and Cao, K and Savadkohighodjanaki, M and Zhang, YJ and Jun, H and Ichii, A and Lee, JY and Soma, S and Medhat, YK and Saido, TC and Igarashi, KM},
title = {Early dopamine disruption in the entorhinal cortex of a knock-in model of Alzheimer's disease.},
journal = {Nature neuroscience},
volume = {},
number = {},
pages = {},
pmid = {42026254},
issn = {1546-1726},
support = {A2019380S//BrightFocus Foundation (BrightFocus)/ ; A2022018F//BrightFocus Foundation (BrightFocus)/ ; BRFSG-2017-04//Brain Research Foundation (BRF)/ ; JPMJPR2481//MEXT | Japan Science and Technology Agency (JST)/ ; AARF-22-923955/ALZ/Alzheimer's Association/United States ; },
abstract = {The entorhinal cortex is a critical brain area for memory formation, while also the region exhibiting the earliest histological and functional alterations in Alzheimer's disease (AD). The entorhinal cortex therefore has been long hypothesized as one of the originating brain areas of AD pathophysiology, although circuit mechanisms causing its selective vulnerability remain poorly understood. Here we show that dopamine neurons projecting their axons to the lateral entorhinal cortex (LEC), critical for memory formation in healthy brains, become dysfunctional from the early pathological stage and cause associative memory impairments in amyloid precursor protein knock-in mice. Dopamine dysfunction led to the disruption of associative memory encoding of LEC layer 2/3. Optogenetic reactivation of LEC dopamine fibers rescued associative learning behavior. L-DOPA treatment restored memory encoding of LEC neurons and associative memory of amyloid precursor protein knock-in mice. These results suggest early dysfunction of LEC-projecting dopamine neurons underlie memory impairment in AD from early stages, pointing to a need for clinical investigation of LEC dopamine in patients with AD.},
}

@article {pmid42026868,
year = {2026},
author = {Huang, J and Wang, YB and Wu, J and Qian, PJ and Shao, J and Cao, DD and Liu, Y and Luo, ZG},
title = {SEC62-mediated ER-Phagy activation alleviates Alzheimer's disease pathology and restores cognitive function in 5×FAD mice.},
journal = {Molecular therapy : the journal of the American Society of Gene Therapy},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.ymthe.2026.04.037},
pmid = {42026868},
issn = {1525-0024},
abstract = {Alzheimer's disease (AD) is a common age-related neurodegenerative disorder. Previous studies have shown that patients with AD exhibit dysregulation of endoplasmic reticulum (ER) homeostasis in the brain, such as ER stress and ER damage. As a type of selective autophagy that specifically clears damaged ER, ER-phagy (endoplasmic reticulum-phagy) plays a key role in ER quality control, but the role in AD progression remains elusive. In this study, we found that ER homeostasis is severely disrupted in the pathological state of AD, characterized by enhanced ER stress response, the presence of ER damage, and concurrent defects in ER-phagy function. Notably, some receptors mediating ER-phagy were decreased in neurons differentiated from induced pluripotent stem cells (iPSCs) derived from AD patients and in 5×FAD mouse samples. Interestingly, overexpression of the ER-phagy receptor SEC62 in the brain of 5×FAD mice via intrathecal AAV injection markedly alleviated disease phenotypes, including β-amyloid (Aβ) plaque deposition, neuroinflammation, and cognitive impairment. These results indicate that restoring ER-phagy activity provides a potential strategy for the treatment of AD.},
}

@article {pmid41840370,
year = {2026},
author = {Gönüllü, S and Aydın, Ş and Çelik, H and Çelik, O and Küçükler, S and Topal, A and Akay, R and Yıldız, MO and Alım, B and Özdemir, S},
title = {Milk-derived miR-126-3p-loaded small extracellular vesicles attenuate amyloid-β-induced cellular stress in a neuroblastoma cell model.},
journal = {BMC neuroscience},
volume = {27},
number = {1},
pages = {},
pmid = {41840370},
issn = {1471-2202},
abstract = {UNLABELLED: Alzheimer’s disease (AD) is characterized by progressive neurodegeneration driven by amyloid-β (Aβ)–associated oxidative stress, mitochondrial dysfunction, and dysregulated inflammatory signaling. Although microRNAs (miRNAs) represent promising regulators of these interconnected pathways, their therapeutic application is limited by instability and inefficient cellular delivery. In this study, the cytoprotective potential of milk-derived small extracellular vesicles (sEVs) loaded with miR-126-3p was evaluated in an Aβ-induced SH-SY5Y neuroblastoma cell model. sEVs were isolated and characterized according to MISEV guidelines, loaded with synthetic miR-126-3p, and administered to Aβ-induced cells. miR-126-3p–enriched sEVs significantly attenuated Aβ-induced oxidative stress, as evidenced by normalization of ROS, LDH, GPX1, MDA, and SOD levels, while naïve sEVs exerted only partial effects. At the transcriptional level, miR-126-3p delivery restored stress-responsive gene expression patterns by reducing ICAM1 and TNF-α expression and normalizing BDNF levels, reflecting modulation of neuron-intrinsic inflammatory signaling rather than tissue-level neuroinflammation. Markers of cytoskeletal and mitochondrial stress, including intracellular NfL, cytochrome c, 8-OHdG, TFAM, PINK1, and DNM1L, were also significantly reduced following miR-126-3p–loaded sEV treatment, indicating improved cellular homeostasis under amyloid stress. Furthermore, intracellular tau-related markers and Aβ1–40 accumulation were attenuated, consistent with suppression of Aβ-triggered pathological signaling cascades. Collectively, these findings demonstrate that sEV-mediated miR-126-3p delivery confers robust cytoprotective effects at the cellular level in a neuroblastoma model. While extrapolation to in vivo neurodegeneration requires caution, the results highlight milk-derived sEVs as a biocompatible and scalable platform for miRNA-based modulation of AD-relevant cellular stress pathways.

GRAPHICAL ABSTRACT: [Image: see text]},
}

@article {pmid42020180,
year = {2026},
author = {Tong, FF and Huang, RQ and Gao, Y and Luo, QQ and Chen, YP and Xu, GZ},
title = {[Epidemiological studies of the association between dyslipidemia and Alzheimer's disease].},
journal = {Zhonghua liu xing bing xue za zhi = Zhonghua liuxingbingxue zazhi},
volume = {47},
number = {4},
pages = {767-774},
doi = {10.3760/cma.j.cn112338-20250727-00528},
pmid = {42020180},
issn = {0254-6450},
mesh = {*Alzheimer Disease/epidemiology ; Humans ; *Dyslipidemias/epidemiology/complications ; Risk Factors ; },
abstract = {Alzheimer's disease (AD), as the representative type of dementia among neurodegenerative diseases, has become a major challenge in the field of global public health. Dyslipidemia is considered an acquired risk factor for AD, and both are progressive diseases with long developmental periods, making dyslipidemia a potential predictor of future AD occurrence. Therefore, preventing dyslipidemia is of great significance for the prevention and treatment of AD. Given the global epidemiological background of AD, this article aims to systematically review the association between dyslipidemia and AD, providing theoretical support for the prevention and control of both conditions.},
}

*Alzheimer Disease/epidemiology
Humans
*Dyslipidemias/epidemiology/complications
Risk Factors

@article {pmid42020356,
year = {2026},
author = {Zou, Z and Chen, J and Li, J and Chen, Y},
title = {The iron-energy metabolism axis in Alzheimer's pathogenesis: from mechanisms to interventions.},
journal = {Cell death discovery},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41420-026-03034-w},
pmid = {42020356},
issn = {2058-7716},
abstract = {Alzheimer's disease (AD) is a neurodegenerative disorder with a complex, multifactorial pathogenesis. Growing evidence implicates disturbances in cellular energy metabolism and iron dyshomeostasis as interlinked contributors to pathology. Within this framework, iron accumulation may act as an upstream regulator in certain contexts and stages, while in others it emerges downstream and amplifies ongoing injury. As iron is an essential cofactor for mitochondrial respiration and the tricarboxylic acid cycle, iron imbalance can compromise ATP production and disrupt glucose metabolism, exacerbating neuronal energy deficits. The interplay among iron accumulation, oxidative stress, and neuroinflammation can create vicious cycles that reprogram cellular metabolism and disrupt the critical metabolic coupling between neurons and glial cells. This review synthesizes recent advances in understanding the iron-energy metabolism axis in AD, delineates mechanisms by which iron imbalance precipitates mitochondrial dysfunction and glucose metabolic impairments, and evaluates how these deficits synergize with neuroinflammation and proteinopathy across disease stages. Finally, we appraise emerging therapeutic strategies targeting iron overload and metabolic pathways, discuss their stage-dependent risks and benefits, and outline the need for biomarker-guided approaches to optimize patient selection and treatment timing.},
}

@article {pmid42020790,
year = {2026},
author = {Ferreira, AFF and Feng, ZP and Sun, HS and Britto, LRG},
title = {Inhibiting the transient receptor potential melastatin 2 channel in microglia: current evidence and therapeutic potential in neurological disorders.},
journal = {Acta pharmacologica Sinica},
volume = {},
number = {},
pages = {},
pmid = {42020790},
issn = {1745-7254},
abstract = {Microglia, the resident immune cells of the central nervous system, play a pivotal role in neuroinflammation and is a key contributor to the onset and progression of various neurological and neurodegenerative diseases. The Transient Receptor Potential Melastatin 2 (TRPM2), a non-selective calcium channel, has emerged as a sensor linking oxidative stress responses and calcium influx. It is expressed in many tissues and cells, including neurons, astrocytes, and microglia. TRPM2 represents one of the molecular mediators regulating microglial activity and function, cytokine production, and microglia-neuron communication. Growing evidence suggests that TRPM2 contributes to the pathological mechanisms underlying diseases such as ischemic stroke, Alzheimer's disease, Parkinson's disease, epilepsy, and neuropathic pain. However, most of the studies mainly explored the TRPM2 involvement in cell death, which has been reviewed by some other authors. In this review, we compile and discuss findings from in vivo and in vitro studies evaluating the role of TRPM2, with a specific focus on its influence over microglial function and neuroinflammatory responses, a field that has been poorly explored. We gathered information from studies reporting, in stroke models, that both pharmacological inhibition and genetic deletion of TRPM2 reduced infarct volume, improved behavioral outcomes, and diminished glial reactivity. In models of neurodegeneration, TRPM2 modulation shows promising effects on neuronal survival and microglial phenotype. In neuropathic pain models, TRPM2 was found to mediate microglial activation and the release of pro-inflammatory mediators, contributing to pain hypersensitivity. However, findings in epilepsy models reveal a more complex picture, with TRPM2 deficiency producing either neuroprotective or deleterious outcomes, highlighting the need for further studies. Although most studies to date support a pathogenic role for TRPM2 in microglia-mediated neuroinflammation, some limitations were highlighted, as the non-selective pharmacological inhibitors available, the inclusion of only males in the majority of studies, and the use of a global TRPM2 knockout. Only two studies employed conditional genetic models to promote specific TRPM2 deletion from microglia, with promising findings. Overall, current evidence indicates TRPM2 as a promising modulator of microglia, with broad implications for the treatment of neurological disorders characterized by chronic inflammation.},
}

@article {pmid42021568,
year = {2026},
author = {Li, Z and Ge, R and Zhao, Z and Xiao, H and Du, C and Lai, Y and Wang, L},
title = {From Bio-Interface Materials to Neural Integration: The Next-Generation Brain-Machine Interfaces Powered by Hydrogels.},
journal = {Advanced materials (Deerfield Beach, Fla.)},
volume = {},
number = {},
pages = {e23422},
doi = {10.1002/adma.202523422},
pmid = {42021568},
issn = {1521-4095},
support = {22322803//National Natural Science Foundation of China/ ; 22375047//National Natural Science Foundation of China/ ; 22361162607//International Cooperation and Exchanges NSFC/ ; 20240305028YY//Key Research Development Program of Jilin Province/ ; 2022YFB3804905//National Key Research and Development Program of China/ ; 2022YFB3804900//National Key Research and Development Program of China/ ; //Graduate Innovation Fund of Jilin University/ ; FZ2025038//State Key Laboratory of New Textile Materials and Advanced Pro- cessing/ ; },
abstract = {Brain-machine interfaces (BMIs), which serve as revolutionary tools for neural recording, modulation, and rehabilitation, are highly dependent on the biocompatibility and mechanical suitability of their electrode materials. Although traditional metal electrodes possess excellent conductivity, their inherent rigidity causes a substantial mechanical mismatch with soft neural tissue, leading to chronic inflammatory responses and poor long-term stability. The emergence of hydrogel electrodes has provided a breakthrough solution to this fundamental limitation. Hydrogels, characterized by their softness, high ionic conductivity, and tissue-like compliance, offer a viable solution to mitigate these issues. This review systematically explores the material properties of hydrogel-integrated BMIs, providing an in-depth investigation of key hydrogel characteristics, including toughness, adhesion, conductivity, and biocompatibility. Additionally, hydrogel-based BMIs are categorized into non-invasive and invasive systems, each defined by its characteristic operational principles and signal-acquisition mechanisms. The study further reviews critical issues, including surgical implantation strategies, multimodal data fusion, integration of artificial intelligence, as well as system integration and clinical translation. From a therapeutic perspective, this work highlights the application of BMIs in treating neurological disorders such as Alzheimer's disease, Parkinson's disease, epilepsy, stroke, neuropathic pain, and depression. Furthermore, this review critically examines the persistent challenges faced by hydrogel-based BMIs and proposes innovative strategies for future development. Ultimately, it outlines a developmental roadmap for next-generation hydrogel-based biotherapeutic technologies aimed at achieving high-fidelity, stable and clinically translatable BMI systems.},
}

@article {pmid42021966,
year = {2026},
author = {Tabi, YA and Meyer, EC},
title = {Autoimmune diseases are associated with increased neurodegenerative and cerebrovascular risk, while systemic corticosteroid exposure shows limited neurodegenerative and modest vascular associations.},
journal = {IBRO neuroscience reports},
volume = {20},
number = {},
pages = {596-608},
pmid = {42021966},
issn = {2667-2421},
abstract = {Systemic autoimmune diseases (AIDs), characterized by chronic peripheral inflammation and frequent vascular comorbidity, are increasingly linked to adverse central nervous system (CNS) outcomes; however, comparative evidence across diverse AIDs and clarification of the roles of vascular burden, inflammatory activity, and immunomodulatory therapy remain limited. Using the TriNetX Global Collaborative Network, we conducted a sequence of retrospective, propensity score-matched cohort experiments in adults aged 50-85 years to quantify incident Parkinson's disease (PD), Alzheimer's disease (AD), transient ischemic attack (TIA), and ischemic stroke across 22 AIDs and to evaluate therapy- and inflammation-stratified risk patterns. In the primary disease-control analysis (Experiment 1 A), AID diagnosis was associated with broadly elevated neurodegenerative and cerebrovascular risk, with stronger and more consistent associations for TIA and ischemic stroke than for PD and AD. To probe robustness, we repeated analyses under tighter control of baseline vascular burden (Experiment 1B: additional matching on circulatory-system diagnoses) and under treatment balancing (Experiment 1 C: additional matching on immune-suppressant exposure). Vascular matching substantially attenuated many associations, particularly for AD, whereas immune-suppressant matching did not materially erase the pervasive cerebrovascular excess. Within-disease CRP stratification (Experiment 2; low vs elevated CRP) did not yield a uniform neurodegenerative gradient but identified a disease-dependent ischemic vulnerability axis in selected inflammatory phenotypes. In treatment substudies, systemic cortisone exposure (Experiment 3) showed little association with PD/AD risk but a modest, heterogeneous increase in TIA/ischemic stroke. Medication-specific strata (Experiment 4) revealed stronger but directionally variable separations, consistent with confounding by indication and severity. Together, these findings position systemic autoimmunity as a robust marker of heightened cerebrovascular risk and a more phenotype-dependent correlate of neurodegenerative risk, supporting intensified vascular surveillance in high-risk AID populations and mechanistic work disentangling inflammation, comorbidity, and treatment.},
}

@article {pmid42022334,
year = {2026},
author = {Bhagunde, P and Penner, N and Willis, BA and Bell, R and Sachdev, P and Charil, A and Irizarry, MC and Hersch, S and Reyderman, L},
title = {Pharmacokinetic/pharmacodynamic analyses of plasma pathophysiology biomarkers in subjects with early Alzheimer's disease following lecanemab treatment.},
journal = {Alzheimer's & dementia (New York, N. Y.)},
volume = {12},
number = {},
pages = {e70246},
pmid = {42022334},
issn = {2352-8737},
abstract = {INTRODUCTION: Lecanemab, a novel monoclonal antibody targeting both neurotoxic amyloid beta (Aβ) protofibrils and Aβ plaques, substantially reduces markers of amyloid and significantly slows clinical decline on multiple measures of cognition and function in early AD in Phase 2 (Study 201) and Phase 3 (Study 301; Clarity AD) studies. In these clinical studies, several plasma biomarkers showed improvements comparing lecanemab with placebo. Herein, we utilized modeling and simulation to evaluate the long-term effects of lecanemab on pathophysiology biomarkers in plasma.

METHODS: Plasma Aβ42/40 ratio, tau phosphorylated at threonine 181 (p-tau181), and glial fibrillary acidic protein (GFAP) data were pooled from lecanemab Phase 2 and 3 studies. Individual serum lecanemab exposure estimated using a population pharmacokinetic model was correlated with plasma biomarker concentrations using indirect response pharmacokinetic/pharmacodynamic (PK/PD) models. Simulations were conducted to evaluate the effect of lecanemab (10 mg/kg IV every 2 weeks, LEC10-BW) after 4 years of continuous treatment, discontinuation after 18 months of treatment or transitioning to less frequent dosing at 18, 24, or 30 months.

RESULTS: PK/PD models describing the change in plasma biomarker levels over time in response to lecanemab treatment were developed, and simulations demonstrated that plasma biomarkers reverted toward pretreatment baseline after cessation of lecanemab treatment, with an average re-accumulation half-life of approximately 1 to 1.5 years, which was faster than amyloid plaque re-accumulation measured by positron emission tomography. Simulations illustrated transitioning to a lecanemab monthly dosing regimen was sufficient to stabilize plasma biomarker concentrations at levels consistent with ongoing inhibition of amyloid pathology and neuroinflammation.

DISCUSSION: PK/PD model simulations demonstrated that plasma biomarkers serve as early indicators of amyloid accumulation and downstream effects. Plasma biomarker simulations suggest the need for ongoing lecanemab treatment even after amyloid plaque clearance. Transition to a less frequent monthly IV regimen at 18 months was shown to maintain the changes in plasma biomarker levels consistent with lecanemab efficacy.},
}

@article {pmid42022743,
year = {2026},
author = {Dai, D and Chen, J and Guo, X and Sun, J and Yi, H},
title = {Mechanistic research on the vestibular-hippocampal pathway in neurodegenerative diseases: an integrative perspective from molecular to behavioral levels.},
journal = {Frontiers in neuroscience},
volume = {20},
number = {},
pages = {1779268},
pmid = {42022743},
issn = {1662-4548},
abstract = {This paper systematically reviews the pivotal role and bidirectional regulatory mechanisms of the Vestibular-hippocampal pathway in the onset and progression of neurodegenerative diseases (such as Alzheimer's disease), focusing on the common comorbidity of vestibular dysfunction and cognitive decline. Evidence spanning molecular to behavioral levels indicates that vestibular signal loss can induce hippocampal atrophy and spatial memory impairment through neuroinflammation, impaired synaptic plasticity, and disrupted theta rhythms. Conversely, hippocampal degeneration further impairs vestibular information integration, creating a vicious cycle. Intervention approaches such as vestibular rehabilitation, cognitive training, and neurostimulation show potential for slowing co-morbidity progression. Future research should focus on developing animal models simulating vestibular-neurodegenerative co-morbidity, conducting longitudinal clinical validation using multimodal imaging and electrophysiology techniques, and optimizing neuromodulation strategies and targeted molecular interventions to advance this mechanism toward early diagnosis and precision treatment.},
}

@article {pmid42022958,
year = {2026},
author = {Chien, SC and Chien, YC and Wang, HJ and Chen, JC},
title = {A ZIF-8-modified electrochemical biosensor for sensitive Aβ aggregation monitoring and Alzheimer's disease drug screening.},
journal = {RSC advances},
volume = {16},
number = {23},
pages = {20855-20865},
pmid = {42022958},
issn = {2046-2069},
abstract = {Alzheimer's disease (AD) is an irreversible neurodegenerative disorder driven by the abnormal aggregation of β-amyloid (Aβ) into oligomers, fibrils, and plaques. Current therapeutic strategies primarily alleviate symptoms but struggle to prevent aggregation due to the dynamic nature of Aβ species and prolonged drug development cycles. Sensitive and real-time monitoring of Aβ structural transitions is therefore essential for understanding disease progression and evaluating potential inhibitors. In this study, we developed a ZIF-8-modified electrochemical biosensor capable of translating Aβ42 conformational changes into quantifiable current signals, providing a promising platform for monitoring dynamic aggregation. The aggregation behavior of Aβ42 was systematically characterized using dynamic light scattering (DLS), electrochemical measurements, and Thioflavin T (ThT) fluorescence combined with ultrafiltration. A critical transition from the lag to the growth phase was observed at 24 h, with aggregates exceeding ∼60 nm undergoing irreversible fibrillization. The ZIF-8-modified electrochemical sensor detected early-stage structural rearrangements with superior sensitivity compared to conventional ThT fluorescence, revealing subtle oligomer formation. Quantitative current measurements allowed continuous monitoring of aggregation kinetics, highlighting the temporal resolution of the platform. Validation experiments with curcumin treatment demonstrated strong inhibitory effects between 18 and 24 h, delaying fibrillization, reducing late-stage β-sheet accumulation, and decreasing aggregate size by approximately 25%. In addition, the sensor successfully distinguished minor differences in structural transitions under varying inhibitor concentrations, demonstrating its capability for high-resolution, real-time assessment of aggregation dynamics and drug efficacy. This ZIF-8-modified electrochemical biosensor provides high-sensitivity, dynamic monitoring of Aβ42 aggregation and drug-induced inhibition, offering a valuable tool for mechanistic studies of protein aggregation pathology. By enabling early detection of structural transitions and real-time evaluation of inhibitors, this platform has the potential to accelerate therapeutic screening and improve the development of effective interventions for AD.},
}

@article {pmid42023276,
year = {2026},
author = {Kuan, JH and Raghavan, RS and Koh, DLW and Tan, WY and Iezhitsa, I and Agarwal, R},
title = {Navigating the cholesterol maze: Key insights on use of statins in neurodegenerative disorders.},
journal = {Neuroprotection (Chichester, England)},
volume = {4},
number = {1},
pages = {30-47},
pmid = {42023276},
issn = {2770-730X},
abstract = {Neurodegenerative diseases such as Alzheimer's (AD), Parkinson's (PD), Huntington's (HD), and multiple sclerosis (MS) involve progressive neuronal loss driven by dysregulated neurotransmission, neuroinflammation, oxidative stress, and mitochondrial dysfunction. Cholesterol metabolism has emerged as a critical factor involved with both central and peripheral dysregulation contributing to pathology. This review synthesizes current evidence on cholesterol's role in neurodegeneration and evaluates the therapeutic potential of statins, which act via cholesterol-dependent and other pleiotropic mechanisms. A PubMed search covering 1985-2025 publications was conducted using terms related to neurodegenerative diseases, statins, cholesterol metabolism, neuroinflammation, oxidative stress, mitochondrial dysfunction, and neuroprotection. Studies were selected to highlight mechanistic insights into cholesterol regulation in the nervous system and clinical data on statin use. Neuronal loss in neurodegeneration is driven by processes including excitotoxicity, inflammation, and mitochondrial dysfunction. Excessive reactive oxygen species activate apoptotic pathways involving BAX, BAK, and p53. Dysregulated cholesterol metabolism is a significant contributor: In AD, the ApoE allele ε4 (ApoE4) links elevated cholesterol to amyloid-β (Aβ) accumulation and cognitive decline; in PD, cholesterol shows mixed effects, with some studies suggesting protection and others linking high levels to α-synuclein aggregation and mitochondrial impairment. In HD reduced cholesterol biosynthesis correlates with neuronal loss, while MS associates with elevated cholesterol and cognitive dysfunction. Statins, widely used cholesterol-lowering agents, reduce Aβ production, enhance its clearance, and improve synaptic function. Beyond lipid lowering, they exert anti-inflammatory, antioxidant, and anti-apoptotic effects. Clinical outcomes remain mixed, with benefits influenced by statin type, dose, treatment duration, disease stage, and patient genetics. Statins show multifaceted neuroprotective potential through cholesterol-dependent and independent pathways. While preclinical data are encouraging, clinical evidence is heterogeneous. Long-term, stratified trials are needed to clarify efficacy, and tailoring therapy to disease-specific mechanisms may offer a viable strategy for mitigating neurodegeneration and enhancing neuronal survival.},
}

@article {pmid42023629,
year = {2026},
author = {Li, Y and Li, S and Ma, J and Zhao, J and Ning, N and Sun, J},
title = {The role of synaptic plasticity in Alzheimer's disease: from molecular mechanisms to therapeutic targets.},
journal = {Folia neuropathologica},
volume = {64},
number = {1},
pages = {1-11},
doi = {10.5114/fn.2025.156508},
pmid = {42023629},
issn = {1509-572X},
mesh = {*Alzheimer Disease/physiopathology/pathology/metabolism/therapy ; Humans ; *Neuronal Plasticity/physiology ; Animals ; tau Proteins/metabolism ; Amyloid beta-Peptides/metabolism ; },
abstract = {Alzheimer's disease (AD) is characterized by a complex pathophysiology, involving abnormal aggregation of amyloid b (Ab) and tau proteins, neuroinflammatory responses, and significant synaptic dysfunction, which collectively contribute to cognitive decline. This review offers a novel perspective by focusing on the pivotal role of synaptic plasticity in the pathogenesis of AD, underscoring its potential as a therapeutic target. The study uniquely synthesizes current molecular and clinical research to illustrate how Ab and tau pathologies disrupt synaptic signaling and structure, further exacerbated by neuroinflammation. We explore both pharmacological interventions, such as BACE1 inhibitors and tau stabilizers, and non-pharmacological strategies, including cognitive therapy and neuromodulation techniques, which have shown promise in modulating synaptic plasticity and slowing cognitive deterioration. Despite these advancements, the field faces significant challenges, including the complexity of AD's underlying mechanisms and limitations in early diagnosis. This review not only highlights the significance of synaptic plasticity in AD but also proposes future research directions that could lead to innovative therapeutic approaches, offering new hope for effective treatment strategies.},
}

*Alzheimer Disease/physiopathology/pathology/metabolism/therapy
Humans
*Neuronal Plasticity/physiology
Animals
tau Proteins/metabolism
Amyloid beta-Peptides/metabolism

@article {pmid42024020,
year = {2026},
author = {Chun, H and Lee, HW and Hong, SB and Ha, SS and Yoon, KJ},
title = {Home-based transcranial photobiomodulation improves cognitive function in mild cognitive impairment due to Alzheimer's disease: A randomized, double-blind, placebo-controlled confirmatory trial.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261443973},
doi = {10.1177/13872877261443973},
pmid = {42024020},
issn = {1875-8908},
abstract = {BackgroundAlzheimer's disease (AD) is a progressive neurodegenerative disorder in which early bioenergetic dysfunction is increasingly implicated in its pathogenesis. Transcranial photobiomodulation (tPBM), a non-invasive neuromodulation using near-infrared light, has shown promise in improving cerebral metabolism and cognitive function.ObjectiveTo assess the safety and efficacy of a home-administered tPBM intervention in individuals with mild cognitive impairment (MCI) due to AD.MethodsIn this randomized clinical trial, 80 participants meeting the NIA-AA criteria for MCI due to AD were recruited. Participants self-administered a tPBM device emitting 808 nm near-infrared light over the bilateral dorsolateral prefrontal cortex, six times weekly for 12 weeks. The primary outcome was the change in MoCA-K score from baseline to week 13. Secondary outcomes included K-MMSE2, CERAD-K, and GDepS scores.ResultsActive tPBM significantly improved cognitive performance compared with the placebo. Mean MoCA-K scores increased by 3.87 ± 2.51 points in the active group versus a 0.74 ± 2.85 point decline in the placebo group (p < 0.001). K-MMSE2 scores improved significantly (p < 0.001). CERAD-K showed a significant between-group difference at week 13 (p < 0.001), while GDepS scores remained unchanged. No device-related adverse events occurred, and adherence to home-based treatment was high.Conclusions12 weeks of home-administered tPBM safely and significantly improved cognitive function in individuals with MCI due to AD. The observed benefits are consistent with enhanced mitochondrial metabolism, cerebral perfusion, and synaptic efficiency. These findings support tPBM as a promising, non-pharmacological treatment for MCI due to AD and as a preventative strategy against AD.Trial RegistrationKorean Clinical Research Information Service (CRiS), https://cris.nih.go.kr, KCT0011155.},
}

@article {pmid42024084,
year = {2026},
author = {Xie, M and Niu, X and Sun, F and Shi, L},
title = {Transcriptome-based identification and experimental validation of a key gene in Alzheimer's disease using dermal fibroblasts.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261443968},
doi = {10.1177/13872877261443968},
pmid = {42024084},
issn = {1875-8908},
abstract = {BackgroundAlzheimer's disease (AD) is a neurodegenerative disorder primarily characterized by progressive cognitive impairment and neuronal damage. The pathogenesis of AD is complex and involves multiple pathological processes. Currently, effective methods for early diagnosis and treatment are lacking.ObjectiveTo identify key pathogenic genes and investigate their roles in Alzheimer's disease, we analyzed transcriptomic data from dermal fibroblasts of AD patients, aiming to assess their potential as novel biomarkers and therapeutic targets.MethodsTranscriptomic data from AD patient and control-derived dermal fibroblasts (DFs) were analyzed to identify differentially expressed genes. Key genes were screened using bioinformatics and a random forest algorithm. ceRNA analysis was performed to explore miRNA-mRNA interactions. The candidate gene SRSF5 was validated via overexpression and knockdown, followed by qPCR, western blotting, and reactive oxygen species (ROS) assays. The role of SRSF5 in endoplasmic reticulum (ER) stress was evaluated by measuring ER stress markers and cellular stress responses.ResultsTranscriptomic analysis revealed significant upregulation of SRSF5 in AD DFs. ceRNA analysis identified miRNAs regulating SRSF5 in AD. Overexpression of SRSF5 led to reduced neuronal proliferation, increased apoptosis, elevated ROS levels, and activation of ER stress markers (CHOP, GRP78, XBP1). SRSF5 knockdown alleviated these effects.ConclusionsSRSF5 may drive AD pathogenesis via ER and oxidative stress, serving as a potential biomarker and therapeutic target for early diagnosis and intervention.},
}

@article {pmid42024119,
year = {2026},
author = {Shan, A and Xu, C and Chen, R and Han, X and Sun, W and Yao, Q and Wang, X and Luan, H and Li, S and Wen, B and Cui, T and Guo, J and Lian, Q and Sun, Y and Li, C and Jia, H and Ma, H and Lv, S and Sun, Q and Wei, C},
title = {Alterations in choroid plexus volume associated with butylphthalide treatment in mild cognitive impairment: Data from a randomized, placebo-controlled study.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261443718},
doi = {10.1177/13872877261443718},
pmid = {42024119},
issn = {1875-8908},
abstract = {BackgroundThe choroid plexus (ChP) is increasingly recognized as an essential component in the pathogenesis of cognitive impairment associated with Alzheimer's disease. DL-3-n-butylphthalide (NBP) has been confirmed to exert neuroprotective effects through multiple pathways and thereby enhance cognitive function. However, the role of NBP in the ChP volume remains unclear at present.ObjectiveThis trial aimed to explore the clinical efficacy of NBP in patients with mild cognitive impairment (MCI) and its corresponding ChP imaging characteristics.MethodsThis randomized, double-masked, placebo-controlled study included 270 MCI patients, randomly assigned in a 1:1 ratio to receive either NBP or placebo. Concurrently, all participants received clinical cognitive evaluations and 3D T1-weighted magnetic resonance imaging scans at both baseline and post-treatment phases. The objective was to evaluate the efficacy of 12-month NBP treatment on cognitive impairment and investigate the neuroimaging correlates of NBP therapy, focusing specifically on longitudinal alterations in ChP.ResultsThe NBP treatment significantly improved the cognitive symptoms of MCI patients, which was strongly correlated with the decrease in ChP volume in the drug group. Moreover, subgroup analysis indicated that cognitive enhancement was closely related to changes in ChP volume in the effective group. Mediation effect analysis revealed that ChP volume partially mediated the enhancement of cognitive symptoms in MCI patients undergoing NBP treatment.ConclusionsThis research provided evidence that NBP may improve cognitive symptoms in MCI patients by regulating changes in ChP volume, as well as offered insight into identifying early neuroimaging markers of MCI and drug targets for NBP.Clinical trial registry nameEfficacy and safety of butylphthalide on patients with mild cognitive impairment; Registration number: ChiCTR1800018362.},
}

@article {pmid42024241,
year = {2026},
author = {Alım, Z and Demir, Y},
title = {Evaluation of pyrimidine-based compounds as AChE and BChE inhibitors: in vitro inhibition, molecular modeling, and statistical evaluation.},
journal = {Naunyn-Schmiedeberg's archives of pharmacology},
volume = {},
number = {},
pages = {},
pmid = {42024241},
issn = {1432-1912},
abstract = {Alzheimer's disease (AD) is a neurodegenerative disease characterized by dementia, particularly in older adults. It is a process that is increasing significantly with the aging population worldwide, has yet to be cured, and therefore challenges healthcare systems. The ability of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitors to modulate neurotransmitter levels has made AChE/BChE inhibitors central therapeutic targets in drug development studies for the treatment of AD. Previous studies have demonstrated the beneficial effects of pyrimidine derivatives on cognitive functions and highlighted their high therapeutic potential against neurodegenerative diseases. Considering the pharmacological importance of AChE/BChE inhibitors and pyrimidine derivatives, this study investigated the inhibitory potential of seven different pyrimidine derivatives (1-7) on AChE and BChE using both in vitro and in silico approaches. Analysis of IC50 values indicated that compounds 1-7 (IC50: 14.89-77.70 nM) exhibited strong inhibitory effect. Compound 6 (IC50:14.89 nM) had the strongest inhibitory effect on AChE, while it showed a much weaker inhibitory effect against BChE (IC50: 357 nM), corresponding to an approximately 24-fold selectivity for AChE. Molecular modeling results indicate that compounds 6 and 7 exhibit favorable interactions within the active site of the enzyme. In addition, compounds 1 and 3, which exhibited the strongest inhibitory effects on BChE, appear to display a multiple binding profile with the active site of BChE. Correlation and regression analyses indicated that compounds 1-7 display a structure-activity relationship (SAR) consistent with strong inhibitory potency toward AChE, while showing comparatively weaker inhibition toward BChE.},
}